{"gene":"TRPS1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2001,"finding":"TRPS1 is a nuclear protein that binds GATA sequences but represses (rather than activates) transcription mediated by other GATA factors. Repression does not occur through competition for DNA binding but depends on a C-terminal region related to repressive domains found in Ikaros proteins. Truncating mutations identified in TRPS patients encode dominant inhibitors of wild-type TRPS1 function.","method":"Nuclear localization studies, GATA-dependent reporter assays, domain deletion analysis, transactivation assays in mammalian cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (reporter assays, DNA-binding assays, domain mutagenesis) in a foundational paper; replicated by subsequent work","pmids":["11285235"],"is_preprint":false},{"year":2002,"finding":"Deletion of the GATA-type zinc finger domain of TRPS1 in mice causes absence of vibrissae, facial anomalies, thoracic skeletal defects, and generalized bone dysplasia, directly implicating the GATA zinc finger in bone and hair development.","method":"Conditional knock-in mouse model (TRPS1 GATA domain deletion), histological and skeletal analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic loss-of-function mouse model with specific skeletal and hair phenotypes, replicated in multiple mouse studies","pmids":["12446778"],"is_preprint":false},{"year":2003,"finding":"The dynein light chain LC8a physically interacts with two distinct regions of TRPS1 (residues 635-723 and 1182-1281) and co-localizes with TRPS1 in dot-like nuclear structures. LC8a interaction reduces TRPS1 binding to the GATA consensus sequence (EMSA) and suppresses TRPS1-mediated transcriptional repression in reporter assays.","method":"Co-immunoprecipitation, EMSA, luciferase reporter assay, confocal microscopy","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and EMSA in single lab with multiple orthogonal methods","pmids":["12761050"],"is_preprint":false},{"year":2003,"finding":"RING finger protein RNF4 interacts with TRPS1 (binding region in TRPS1 amino acids 985-1184) via yeast two-hybrid and co-immunoprecipitation from both transfected and native mammalian cells. RNF4 co-localizes with TRPS1 in distinct nuclear structures. RNF4 overexpression inhibits TRPS1 transcriptional repression activity in luciferase reporter assays.","method":"Yeast two-hybrid screen, co-immunoprecipitation, luciferase reporter assay, confocal laser-scanning microscopy","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus reciprocal co-IP from native cells, single lab, multiple orthogonal methods","pmids":["12885770"],"is_preprint":false},{"year":2003,"finding":"TRPS1 overexpression in androgen-dependent LNCaP prostate cancer cells inhibits transcription of a PSA enhancer/promoter-driven luciferase reporter and reduces androgen-induced endogenous PSA secretion. TRPS1 binds to an inverse GATA motif overlapping ARE III in the PSA enhancer.","method":"Luciferase reporter assay, PSA ELISA from conditioned medium, GATA motif analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter plus endogenous protein measurement, single lab","pmids":["14680804"],"is_preprint":false},{"year":2004,"finding":"Two missense mutations in the RRRTRKR motif of TRPS1 (arginine to histidine or cysteine) prevent nuclear translocation of the mutant protein when expressed in COS7 cells, identifying RRRTRKR as the functional nuclear localization signal of TRPS1.","method":"Subcellular localization studies of mutant TRPS1 constructs in COS7 cells, patient mutation identification","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with mutagenesis in cell-based system, single lab","pmids":["14560312"],"is_preprint":false},{"year":2007,"finding":"Trps1 directly represses Stat3 expression by binding to GATA-binding sites in the Stat3 gene promoter. In Trps1-deficient chondrocytes, elevated Stat3 drives increased cyclin D1 and Bcl2, causing diminished proliferation and decreased apoptosis. siRNA-mediated Stat3 depletion in Trps1-deficient chondrocytes normalizes cyclin D1 and Bcl2 levels. Mutation of GATA-binding sites in the Stat3 promoter abrogates Trps1 binding and repression.","method":"Trps1 knockout mouse, siRNA knockdown of Stat3, Trps1 overexpression in ATDC5 cells, mutational analysis of GATA-binding sites in Stat3 promoter, ChIP, Western blot","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including promoter mutagenesis, ChIP, rescue experiments, and genetic KO","pmids":["17997399"],"is_preprint":false},{"year":2007,"finding":"TRPS1 is SUMOylated at multiple sites in vivo and in vitro through interaction with UBC9. SUMOylation at the C-terminal repression domain (primarily K1201/S5, secondarily K1192/S4) is required for TRPS1-mediated transcriptional repression; mutation of both S4 and S5 almost completely abolishes repressive activity.","method":"In vitro and in vivo SUMOylation assays, site-directed mutagenesis of SUMO acceptor sites, luciferase reporter assays, UBC9 overexpression","journal":"Biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of SUMOylation plus mutagenesis and functional reporter assays, single lab but multiple orthogonal methods","pmids":["17391059"],"is_preprint":false},{"year":2008,"finding":"Trps1 interacts specifically with the transactivation domain of Gli3 activator form (Gli3A) but not the repressor form, both in vitro and in vivo. A 185 aa region of Trps1 containing three predicted zinc fingers is sufficient for this interaction. Genetic analysis using mouse models indicates Trps1 and Gli3 repressor activity cooperate in distal chondrocytes and have activating functions in columnar proliferating chondrocytes.","method":"In vitro binding assay, co-immunoprecipitation in vivo, domain mapping with truncated constructs, mouse genetic models (double mutants)","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro binding plus in vivo co-IP plus genetic epistasis in multiple mouse models","pmids":["19389374"],"is_preprint":false},{"year":2008,"finding":"Trps1 directly binds the PTHrP promoter and suppresses PTHrP transcription. Loss of Trps1 leads to expanded PTHrP expression in the growth plate and elongated proliferative zones, demonstrating that Trps1 directly represses PTHrP to regulate chondrocyte organization.","method":"ChIP assay, promoter luciferase assay, quantitative RT-PCR, Trps1 knockout mouse, tibial organ culture","journal":"Bone","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP plus reporter plus KO mouse with in vivo rescue, single lab, multiple methods","pmids":["18456591"],"is_preprint":false},{"year":2008,"finding":"GDF5 induces Trps1 protein upregulation and nuclear translocation via p38 MAPK signaling downstream of ALK6 in ATDC5 chondrocytes. Trps1 acts downstream of GDF5 signaling to promote chondrogenic differentiation and apoptosis; effects are blocked by dominant-negative ALK6 or p38 MAPK inhibitor SB203580.","method":"Treatment with GDF5, dominant-negative ALK6 overexpression, SB203580 inhibitor, Western blot, immunofluorescence, differentiation assays, apoptosis assays","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic inhibition with multiple readouts, single lab","pmids":["18363966"],"is_preprint":false},{"year":2009,"finding":"TRPS1 directly binds the osteocalcin promoter through a GATA binding sequence and represses osteocalcin transcription. Mutation of the GATA binding site in the mouse or human osteocalcin promoter abrogates TRPS1 binding. TRPS1 regulates osteocalcin expression in osteosarcoma cells and primary bone marrow stromal cells, and modulates mineralized bone matrix formation.","method":"Proteomic identification of TRPS1 at OSE2 sequence, EMSA, reporter assays, promoter mutagenesis, ChIP, siRNA knockdown, mineralization assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — proteomic identification, EMSA with mutagenesis, ChIP, and functional mineralization assay, multiple methods in single study","pmids":["19759027"],"is_preprint":false},{"year":2009,"finding":"Trps1 functions downstream of BMP7 in kidney development. BMP7-deficient kidneys show virtual absence of Trps1 expression. BMP7 induces Trps1 and E-cadherin expression and downregulates vimentin in metanephric mesenchymal cells. siRNA knockdown of Trps1 inhibits BMP7-induced mesenchymal-to-epithelial transition.","method":"Trps1 knockout mouse, Bmp7 knockout mouse analysis, in vitro metanephric mesenchymal cell culture with BMP7 treatment, siRNA knockdown, immunofluorescence, in situ hybridization","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (Bmp7 KO reduces Trps1) plus siRNA rescue in cell culture, replicated across KO models","pmids":["19820125"],"is_preprint":false},{"year":2010,"finding":"Trps1 haploinsufficiency promotes TGF-β1-induced EMT and tubulointerstitial fibrosis. Trps1+/- cells have elevated Arkadia (an E3 ubiquitin ligase), increased Smad3 phosphorylation, and decreased Smad7 protein. Arkadia knockdown inhibits TGF-β1-induced EMT in Trps1+/- cells, placing Trps1 upstream of Arkadia-mediated Smad7 degradation.","method":"Trps1 heterozygous knockout mouse, unilateral ureteral obstruction model, siRNA knockdown of Arkadia, immunohistochemistry, Western blot, primary tubular cell culture","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic model plus siRNA rescue, single lab, multiple orthogonal assays","pmids":["20507941"],"is_preprint":false},{"year":2011,"finding":"miR-221/222 target the 3'UTR of TRPS1 to reduce its expression, and TRPS1 inhibits EMT by directly repressing ZEB2 expression. Knockdown of TRPS1 mimics miR-221/222-induced EMT, and TRPS1 overexpression rescues the EMT phenotype. FOSL1/Fra-1 drives miR-221/222 transcription downstream of the RAS/MEK pathway.","method":"3'UTR luciferase reporter assay, TRPS1 knockdown/overexpression, qRT-PCR, migration/invasion assays, Western blot","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — 3'UTR reporter assay confirming direct targeting, knockdown/OE rescue experiments, two papers from same group corroborating findings","pmids":["21673316","21868360"],"is_preprint":false},{"year":2011,"finding":"Trps1 can directly bind the promoters of its target genes in the developing vibrissa follicle to activate transcription (of Wnt inhibitors and transcription factors), in addition to its established role as a transcriptional repressor. Trps1 regulates the Wnt signaling pathway in early hair follicle progenitors.","method":"Microarray hybridization, ChIP on vibrissa follicle tissue, in vivo target gene expression validation in Trps1 GATA domain deletion mice","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus microarray plus in vivo gene expression validation, single lab","pmids":["22115758"],"is_preprint":false},{"year":2012,"finding":"Trps1 directly represses Sox9 expression in the developing hair follicle, as demonstrated by ChIP showing Trps1 occupancy at the Sox9 promoter and functional assays showing that Trps1 loss leads to elevated Sox9 and increased epithelial proliferation.","method":"ChIP, Trps1 GATA domain deletion mouse model (Trps1Δgt), immunofluorescence, proliferation assays","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus genetic KO model, single lab","pmids":["23133399"],"is_preprint":false},{"year":2012,"finding":"Seven RUNX2-targeting miRNAs (miR-23a, miR-30c, miR-34c, miR-133a, miR-135a, miR-205, miR-217) also target TRPS1 through its 3'UTR, effectively blocking maturation of osteoblasts and chondrocytes and redirecting mesenchymal stem cells toward adipogenic fate.","method":"3'UTR reporter assays, miRNA overexpression in osteoblasts and chondrocytes, cell differentiation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3'UTR reporter assays plus differentiation phenotype, single lab","pmids":["22544738"],"is_preprint":false},{"year":2013,"finding":"Trps1 interacts with histone deacetylases Hdac1 and Hdac4, increasing their activity. Loss of Trps1 results in histone H3 hyperacetylation maintained during mitosis, impairing chromatin condensation and HP1 binding, leading to prometaphase arrest. Overexpression of Hdac4 rescues the mitotic defect in Trps1-deficient chondrocytes.","method":"Trps1 knockout mouse, co-immunoprecipitation (Trps1-Hdac1/Hdac4), HDAC activity assays, histone acetylation Western blot, mitotic index analysis, Hdac4 overexpression rescue","journal":"Cell cycle","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP of endogenous complex, HDAC activity assay, genetic rescue experiment, multiple orthogonal readouts","pmids":["23892436"],"is_preprint":false},{"year":2013,"finding":"Loss of Trps1 suppresses ureteric bud branching through activation of TGF-β/Smad3 signaling, including upregulation of Rb1cc1 and Arkadia, increased Smad3 phosphorylation, and decreased Smad7 and c-Ski. Addition of Smad3 inhibitor SIS3 restores branching in Trps1-deficient ureteric buds in organ culture.","method":"Trps1 knockout mouse, DNA microarray of cultured ureteric buds, Western blot, immunohistochemistry, TUNEL, PCNA staining, SIS3 inhibitor rescue in organ culture","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus pharmacological rescue in organ culture, single lab, multiple methods","pmids":["23537899"],"is_preprint":false},{"year":2014,"finding":"Trps1 serves dual context-dependent functions in dentin mineralization: Trps1 is required for odontoblast maturation (supports expression of Alpl and Phospho1 needed to initiate mineralization), while in mature odontoblasts Trps1 represses mineralization-related genes (downregulates phosphate homeostasis genes). Both loss and overexpression of Trps1 impair mineralization.","method":"Stable Trps1-deficient and Trps1-overexpressing odontoblastic cell lines, alkaline phosphatase staining, alizarin red staining, qRT-PCR of target genes","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable cell lines with gain and loss of function, multiple mineralization assays, single lab","pmids":["25128529"],"is_preprint":false},{"year":2015,"finding":"Nuclear cathepsin D (Cath-D) interacts with TRPS1 and they co-localize in the nucleus of ER+ breast cancer cells where both are associated with chromatin. Cath-D enhances TRPS1-mediated transcriptional repression (including of PTHrP) in a non-proteolytic manner. BAT3 controls Cath-D nuclear targeting. Co-silencing of Cath-D and TRPS1 impairs cell cycle progression and soft agar colony formation.","method":"Co-immunoprecipitation, co-localization by microscopy, LexA-VP16 reporter assay, microarray after Cath-D/TRPS1 silencing, siRNA knockdown, soft agar assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus reporter assay plus functional knockdown, single lab, multiple orthogonal methods","pmids":["26183398"],"is_preprint":false},{"year":2016,"finding":"TRPS1 acts as a transcriptional activator of FOXA1 by directly binding the FOXA1 promoter, thereby suppressing EMT. TRPS1 knockdown decreases FOXA1 expression and promotes EMT, migration, invasion, and in vivo metastasis; ectopic FOXA1 expression blocks EMT enhancement caused by TRPS1 silencing. miR-373 binding to the TRPS1 3'UTR reduces TRPS1 expression.","method":"Quantitative proteomics, ChIP, TRPS1 knockdown/overexpression, FOXA1 overexpression rescue, invasion/migration assays, in vivo metastasis model, luciferase 3'UTR assay","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding plus proteomic identification plus functional rescue, single lab","pmids":["26969828"],"is_preprint":false},{"year":2018,"finding":"TRPS1 is a potent repressor of YAP/TEAD-dependent transcription in breast cancer. TRPS1 binds a large set of joint genomic enhancers with YAP and recruits corepressor complexes, reducing H3K27 acetylation. Loss of TRPS1 (identified by genome-wide CRISPR screen) leads to enhancer activation, altered promoter-enhancer interaction landscape, and increased YAP-dependent transcription.","method":"Genome-wide CRISPR screen, ChIP-seq, ATAC-seq, H3K27ac ChIP-seq, Hi-C/promoter-enhancer interaction analysis, TRPS1 knockout","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genome-wide CRISPR screen plus multi-omics (ChIP-seq, ATAC-seq, Hi-C) in single comprehensive study","pmids":["30082728"],"is_preprint":false},{"year":2018,"finding":"TRPS1 associates with the NuRD and coREST histone deacetylation complexes (identified by proteomic and genomic approaches). TRPS1 is required for repressing spurious ER binding and removing histone acetylation at cis-regulatory elements in breast cancer cells, thereby regulating cell proliferation.","method":"Focused siRNA screen (330 chromatin regulators), proteomics (mass spectrometry), ChIP-seq for ER and TRPS1, H3K27ac ChIP-seq, TRPS1 knockdown","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — proteomic identification of complex plus ChIP-seq genomic validation plus functional phenotype, multiple orthogonal methods","pmids":["29895970"],"is_preprint":false},{"year":2018,"finding":"TRPS1 knockdown results in perturbed mitosis, apoptosis, and reduced tumor growth in breast cancer cells. Integrated analysis reveals TRPS1 associates with the NuRD repressor complex and regulates a transcriptional network essential for breast cancer cell survival.","method":"Targeted shRNA screen across 59 cell lines, TRPS1 knockdown, cell cycle/apoptosis assays, transcriptional target analysis, chromatin binding assays, protein interaction studies","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA screen plus chromatin binding plus protein interaction, single lab","pmids":["30380416"],"is_preprint":false},{"year":2018,"finding":"TRPS1 directly inhibits SUZ12 transcription by binding to the SUZ12 promoter (demonstrated by ChIP). Loss of TRPS1 results in increased SUZ12 binding and H3K27 tri-methylation at the CDH1 (E-cadherin) promoter, thereby repressing E-cadherin and promoting EMT.","method":"ChIP assay for TRPS1 at SUZ12 promoter, H3K27me3 ChIP at CDH1 promoter, TRPS1 knockdown/overexpression, Western blot, migration assays","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus epigenetic readout, single lab","pmids":["29471243"],"is_preprint":false},{"year":2019,"finding":"TRPS1 mediates suppression of interferon signaling to promote mammary epithelial proliferation and lactogenic differentiation. TRPS1 loss combined with E-cadherin inactivation causes persistent proliferation of mammary organoids and accelerates mammary tumor formation in mice, demonstrating context-dependent tumor suppressor activity.","method":"In vitro and in vivo Trps1 loss-of-function, mammary organoid culture, conditional mouse knockout models, RNA-seq for interferon pathway genes","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vitro and in vivo loss-of-function models with defined molecular pathway (interferon signaling) and phenotypic rescue","pmids":["31879358"],"is_preprint":false},{"year":2019,"finding":"Trps1 and the Gli3 activator form cooperate to activate Wnt5a expression by binding to an upstream regulatory sequence (URS1) in the Wnt5a promoter, as shown by ChIP and reporter assays. Loss of both Trps1 and Gli3 decreases endogenous Wnt5a mRNA and protein during chondrocyte differentiation.","method":"ChIP, reporter gene assays, Trps1/Gli3 double knockout mouse analysis, Wnt5a mRNA/protein measurement","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter plus genetic epistasis, single lab","pmids":["31550480"],"is_preprint":false},{"year":2019,"finding":"TRPS1 is an important factor for zygotic genome activation during mouse preimplantation development. TRPS1 protein peaks at the two/four-cell stage; Trps1 knockdown reduces developmental rate (~30%), increases ZGA marker genes (MuERV-L, Zscan4d) and decreases H3K4me3 and H3K27me3 histone marks, suggesting TRPS1 normally suppresses ZGA markers through epigenetic regulation.","method":"Trps1 siRNA microinjection into mouse embryos, qRT-PCR of ZGA markers, immunofluorescence for histone marks, embryo developmental rate analysis","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct siRNA knockdown in embryos with histone mark analysis, single lab","pmids":["30712485"],"is_preprint":false},{"year":2021,"finding":"TRPS1 promotes breast carcinogenesis by regulating DNA replication. TRPS1 occupies H3K9me3-marked heterochromatic replication origins and promotes chromatin loading of APC/C, resulting in uncontrolled origin refiring. TRPS1 reads H3K9me3 through its GATA and IKAROS domains. TRPS-related mutations reduce chromatin binding, replication boosting, and tumorigenicity. Overexpression of wild-type but not TRPS-associated mutant TRPS1 drives cancer genome amplifications.","method":"Epigenomic decomposition/ChIP-seq, replication origin analysis, APC/C chromatin loading assay, mutagenesis of GATA/IKAROS domains, overexpression studies, tumor xenograft models","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal genomic and functional approaches, domain mutagenesis, in vivo tumor model","pmids":["33691114"],"is_preprint":false},{"year":2007,"finding":"Overexpression of TRPS1 in DU145 prostate cancer cells decreases expression of antioxidant proteins (superoxide dismutase, protein disulfide isomerase A3, endoplasmin, annexin A2), mitochondria-associated proteins, glycolytic enzymes, and apoptosis-related proteins, suggesting TRPS1 involvement in oxidative stress response.","method":"2D electrophoresis, mass spectrometry of stably inducible TRPS1-expressing DU145 cells vs parental cells","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proteomics without functional validation, single lab, no mechanistic follow-up","pmids":["17467349"],"is_preprint":false},{"year":2010,"finding":"Trps1 directly binds the P2 promoter of Runx1 via its GATA domain and represses Runx1 expression in growth plate chondrocytes, as demonstrated by luciferase reporter assay and ChIP. Runx1 is aberrantly expressed in Trps1-null mouse growth plate cartilage.","method":"DNA array (ATDC5 cells), luciferase promoter assay, ChIP, in situ hybridization in Trps1-null mice","journal":"Experimental and molecular pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter plus in vivo validation in KO mouse, single lab","pmids":["21122804"],"is_preprint":false},{"year":2007,"finding":"TRPS1 mRNA and protein expression in androgen-dependent prostate cancer cells is down-regulated by androgens via the androgen receptor (AR), as demonstrated by androgen withdrawal/castration experiments in prostate cancer xenografts where castration increases TRPS1 protein.","method":"Androgen withdrawal (castration) in xenograft models, quantitative RT-PCR, Western blot/IHC in xenograft tissue","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo hormonal manipulation with protein-level readout, single lab","pmids":["15613454"],"is_preprint":false},{"year":2007,"finding":"TRPS1 forms an AML1-TRPS1 fusion protein in a t(8;21)(q24;q22) leukemia that represses AML1 and GATA-1 transcriptional activity by two mechanisms: competition at cognate DNA-binding sites and physical sequestration of AML1 and GATA-1. The fusion stimulates proliferation of hematopoietic colony-forming cells.","method":"Identification of chimeric gene by molecular cloning, luciferase reporter assay for AML1 and GATA-1 activity, co-immunoprecipitation for physical interaction, hematopoietic colony-forming assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus co-IP plus functional colony assay, single case but multiple methods","pmids":["17244685"],"is_preprint":false},{"year":2012,"finding":"Transcriptional repression of Dspp by Trps1 is the molecular basis for dentinogenesis imperfecta in Col1a1-Trps1 transgenic mice. Sustained high Trps1 levels in odontoblasts directly inhibit the Dspp promoter, reducing DSP and DPP protein levels and impairing dentin mineralization.","method":"Col1a1-Trps1 transgenic mouse, ChIP (Trps1 at Dspp promoter), micro-CT, histology, biochemical analysis of dentin matrix proteins","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus transgenic mouse plus biochemical validation, single lab","pmids":["22508542"],"is_preprint":false},{"year":2016,"finding":"Trps1 directly activates Pde4d transcription by binding to its regulatory elements (shown by ChIP-seq and dual luciferase assay). Trps1 promotes renal tubular epithelial cell proliferation after ischemia-reperfusion injury through the Pde4d/PI3K/AKT signaling pathway; Pde4d knockdown or PI3K inhibition abolishes Trps1-induced proliferation.","method":"ChIP-seq, dual luciferase assay, Trps1 knockdown/overexpression in rats, Pde4d siRNA, wortmannin (PI3K inhibitor), in vivo renal I/R model","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus reporter plus in vivo pharmacological rescue, single lab","pmids":["27466160"],"is_preprint":false},{"year":2014,"finding":"TRPS1 promotes angiogenesis in breast cancer by directly binding the VEGFA promoter (demonstrated by ChIP) to activate VEGFA expression; TRPS1 overexpression increases HUVEC migration and VEGFA levels, while knockdown decreases both.","method":"ChIP assay for TRPS1 at VEGFA promoter, TRPS1 overexpression/knockdown, HUVEC migration assay, VEGFA qRT-PCR, immunohistochemistry for CD31/MVD","journal":"Experimental biology and medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional angiogenesis assay, single lab","pmids":["24595984"],"is_preprint":false},{"year":2024,"finding":"TRPS1 R544Q mutation (enriched in liver metastases of colon cancer) significantly increases CRC invasion and migration in vitro and in vivo through a TRPS1R544Q/ZEB1 axis.","method":"Single-cell exome sequencing, functional in vitro invasion/migration assays, in vivo xenograft, identification of TRPS1-ZEB1 axis","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single-cell sequencing plus functional validation in vitro and in vivo, single lab","pmids":["39307879"],"is_preprint":false},{"year":2021,"finding":"Trps1 regulates Leydig cell proliferation by binding the Srcin1 promoter to regulate its transcription, influencing Src phosphorylation levels, and thereby controlling the Src/Akt/Ccnd1 signaling pathway. Trps1 knockdown suppresses Src and Akt phosphorylation and Ccnd1 expression.","method":"ChIP-seq, ChIP-qPCR for Trps1 at Srcin1 promoter, RNA-seq, Trps1 siRNA knockdown in Leydig cells, Western blot","journal":"Andrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus RNA-seq plus knockdown with signaling readout, single lab","pmids":["34185441"],"is_preprint":false},{"year":2020,"finding":"TRPS1 regulates BCRP (breast cancer resistance protein) expression; TRPS1 overexpression upregulates BCRP while knockdown decreases BCRP, conferring multidrug resistance of breast cancer cells.","method":"TRPS1 overexpression/knockdown, Western blot for BCRP, MTT drug sensitivity assay, immunohistochemistry in 180 breast cancer samples","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression/knockdown with Western blot, no direct promoter binding assay, single lab","pmids":["32695669"],"is_preprint":false},{"year":2020,"finding":"TRPS1 directly represses SerpinB2 expression in osteogenic cells by occupying regulatory elements in the SerpinB2 gene; Trps1 occupancy changes in response to inorganic phosphate (Pi). Transgenic Trps1 overexpression (2.3Col1a1-Trps1) decreases SerpinB2 in osteoblasts and odontoblasts in vivo.","method":"ChIP assay for Trps1 at SerpinB2 regulatory elements, Trps1 overexpressing cell lines, 2.3Col1a1-Trps1 transgenic mice, Western blot, mineralization assay","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus transgenic mouse validation, single lab","pmids":["33022456"],"is_preprint":false},{"year":2022,"finding":"TRPS1 expression in synovial sarcoma is driven at least in part by the SS18-SSX fusion oncoprotein; ChIP-seq shows enrichment of SS18-SSX at the TRPS1 locus with co-localization of RNA pol II and active histone marks, and repression of SS18::SSX in synovial sarcoma cell lines reduces TRPS1 transcript levels.","method":"Immunohistochemistry on 165 synovial sarcoma cases, publicly available gene expression datasets, ChIP-seq data analysis, SS18::SSX knockdown cell line data","journal":"Human pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — bioinformatics/public ChIP-seq reanalysis plus publicly available knockdown data, not performed de novo in this study","pmids":["36162599"],"is_preprint":false}],"current_model":"TRPS1 is an atypical GATA-type transcription factor that primarily acts as a transcriptional repressor by binding GATA consensus sequences and recruiting corepressor complexes (NuRD, coREST) and histone deacetylases (HDAC1, HDAC4); it is SUMOylated at its C-terminal Ikaros-like repression domain to enhance repression, interacts with partners including RNF4, LC8a, and cathepsin D that modulate its activity, and regulates diverse downstream targets (Stat3, PTHrP, Sox9, ZEB2, FOXA1, SUZ12, Runx1, osteocalcin, VEGFA, Dspp, Pde4d) in a context-dependent manner — functioning as a repressor in chondrogenesis, bone, and hair follicle development and as either a repressor or activator in cancer and kidney contexts — while also occupying heterochromatic replication origins to promote APC/C chromatin loading and control DNA replication fidelity."},"narrative":{"mechanistic_narrative":"TRPS1 is an atypical GATA-type transcription factor that functions predominantly as a transcriptional repressor governing cell differentiation in skeletal, hair follicle, kidney, and mammary tissues, and is co-opted in cancer [PMID:11285235, PMID:12446778, PMID:30082728]. It binds GATA consensus sequences through its zinc finger domain but, unlike canonical GATA factors, represses transcription via a C-terminal Ikaros-related domain rather than by competing for DNA occupancy; truncating patient mutations encode dominant inhibitors of wild-type function [PMID:11285235]. Repression is enforced through recruitment of the NuRD and coREST corepressor complexes and the histone deacetylases HDAC1 and HDAC4, lowering histone acetylation at target cis-regulatory elements [PMID:23892436, PMID:29895970]. Repressive activity is enhanced by SUMOylation of the C-terminal domain via UBC9 [PMID:17391059] and modulated by partners that antagonize DNA binding (the dynein light chain LC8a and RNF4) [PMID:12761050, PMID:12885770] or potentiate repression (nuclear cathepsin D) [PMID:26183398]. In chondrogenesis and skeletal development TRPS1 directly represses Stat3, PTHrP, Sox9, Runx1, and osteocalcin to control chondrocyte proliferation, organization, and bone mineralization, while cooperating with the Gli3 activator to regulate Wnt5a [PMID:17997399, PMID:18456591, PMID:23133399, PMID:19759027, PMID:21122804, PMID:31550480]; deletion of its GATA zinc finger in mice causes bone dysplasia and loss of vibrissae [PMID:12446778]. In epithelial and cancer contexts TRPS1 suppresses EMT by repressing ZEB2 and SUZ12 and activating FOXA1, and acts as a potent repressor of YAP/TEAD- and ER-driven transcription required for breast cancer cell proliferation and survival [PMID:21673316, PMID:21868360, PMID:29471243, PMID:26969828, PMID:30082728, PMID:29895970]. TRPS1 also promotes breast carcinogenesis through a non-transcriptional chromatin role: it reads H3K9me3 at heterochromatic replication origins via its GATA and IKAROS domains and drives APC/C chromatin loading, causing origin refiring and genome amplification, an activity lost in TRPS-associated mutants [PMID:33691114]. Beyond these roles, TRPS1 regulates DNA replication fidelity and mitotic chromatin condensation, the latter through HDAC-dependent control of histone acetylation [PMID:23892436, PMID:33691114].","teleology":[{"year":2001,"claim":"Established the foundational paradox that TRPS1, despite binding GATA elements, is a transcriptional repressor acting through an Ikaros-like C-terminal domain rather than DNA-binding competition, and that patient truncations act as dominant inhibitors.","evidence":"Nuclear localization, GATA reporter and DNA-binding assays, domain deletion in mammalian cells","pmids":["11285235"],"confidence":"High","gaps":["Did not identify the corepressor machinery recruited by the Ikaros-like domain","Direct genomic targets unknown at this stage"]},{"year":2002,"claim":"Genetically linked the GATA zinc finger domain to TRPS1's developmental function, showing it is required for bone and hair follicle morphogenesis.","evidence":"Conditional GATA-domain deletion knock-in mouse with skeletal and vibrissae phenotyping","pmids":["12446778"],"confidence":"High","gaps":["Did not define the direct target genes responsible for the phenotypes","Mechanism of repression at target loci unaddressed"]},{"year":2003,"claim":"Identified the first physical partners (LC8a, RNF4) that antagonize TRPS1 DNA binding and repression, indicating its activity is post-translationally tunable.","evidence":"Yeast two-hybrid, reciprocal co-IP from native cells, EMSA, reporter assays, confocal microscopy","pmids":["12761050","12885770"],"confidence":"Medium","gaps":["Physiological contexts where these interactions operate not established","Whether RNF4 modifies TRPS1 enzymatically not resolved here"]},{"year":2004,"claim":"Mapped the functional nuclear localization signal (RRRTRKR), connecting patient mutations to a defect in nuclear import.","evidence":"Subcellular localization of mutant constructs in COS7 cells with patient mutation analysis","pmids":["14560312"],"confidence":"Medium","gaps":["Import receptor mediating NLS recognition not identified"]},{"year":2007,"claim":"Defined TRPS1's mechanism in chondrocytes by showing direct repression of Stat3 controls proliferation and apoptosis via cyclin D1 and Bcl2.","evidence":"Trps1 KO mouse, ChIP, promoter GATA-site mutagenesis, Stat3 siRNA rescue in chondrocytes","pmids":["17997399"],"confidence":"High","gaps":["Corepressor complex at the Stat3 promoter not defined","Generality to other tissues untested"]},{"year":2007,"claim":"Showed SUMOylation of the C-terminal repression domain via UBC9 is required for full repressive activity, revealing post-translational control of TRPS1 function.","evidence":"In vitro and in vivo SUMOylation assays, acceptor-site mutagenesis, reporter assays","pmids":["17391059"],"confidence":"High","gaps":["How SUMOylation mechanistically enhances corepressor recruitment not shown","Desumoylation regulation unaddressed"]},{"year":2007,"claim":"Connected TRPS1 to hormonal and oncogenic contexts: androgen/AR downregulates TRPS1 in prostate cancer, an AML1-TRPS1 fusion sequesters AML1/GATA-1 in leukemia, and TRPS1 alters oxidative-stress proteomes.","evidence":"Castration xenograft, molecular cloning of fusion, reporter and colony assays, 2D-MS proteomics","pmids":["15613454","17244685","17467349"],"confidence":"Medium","gaps":["Oxidative-stress proteome finding (idx 31) is Low-confidence and lacks functional validation","Fusion derived from single leukemia case"]},{"year":2008,"claim":"Revealed TRPS1's context-dependent activator role and skeletal target network: it interacts with the Gli3 activator and directly represses PTHrP, while GDF5/p38 MAPK signaling drives its nuclear accumulation.","evidence":"Co-IP, domain mapping, double-mutant mouse genetics, ChIP, promoter reporters, pharmacological inhibition in ATDC5 cells","pmids":["19389374","18456591","18363966"],"confidence":"High","gaps":["Molecular switch between Gli3 cooperative activation and repression not defined","Direct Gli3-binding interface incompletely mapped"]},{"year":2009,"claim":"Extended the skeletal target repertoire (osteocalcin) and placed TRPS1 downstream of BMP7 in kidney mesenchymal-to-epithelial transition.","evidence":"EMSA, ChIP, promoter mutagenesis, mineralization assays, Bmp7/Trps1 KO mice, siRNA rescue","pmids":["19759027","19820125"],"confidence":"High","gaps":["How BMP7 induces Trps1 transcriptionally not resolved","Direct kidney target genes not all defined"]},{"year":2010,"claim":"Showed TRPS1 dosage controls TGF-β/Smad signaling in kidney fibrosis through Arkadia-mediated Smad7 degradation, and identified Runx1 as a direct repression target.","evidence":"Trps1+/- mouse, ureteral obstruction model, Arkadia siRNA rescue, ChIP and reporter for Runx1 P2 promoter","pmids":["20507941","21122804"],"confidence":"Medium","gaps":["Whether Arkadia is a direct or indirect Trps1 target unclear","Single-lab observations for the fibrosis axis"]},{"year":2011,"claim":"Demonstrated TRPS1 can directly activate transcription in hair follicle progenitors and is itself an EMT-suppressing target of miR-221/222 acting through ZEB2 repression.","evidence":"ChIP plus microarray in vibrissa follicle, GATA-deletion mice, 3'UTR luciferase reporter, knockdown/overexpression rescue","pmids":["22115758","21673316","21868360"],"confidence":"High","gaps":["Determinants of activator versus repressor behavior at a given promoter not defined","Cofactors enabling activation not identified"]},{"year":2012,"claim":"Broadened the developmental target network (Sox9 in hair follicle; Dspp in dentin) and showed multiple RUNX2-targeting miRNAs converge on the TRPS1 3'UTR to control mesenchymal cell fate.","evidence":"ChIP, GATA-deletion and Col1a1-Trps1 transgenic mice, 3'UTR reporters, differentiation assays","pmids":["23133399","22508542","22544738"],"confidence":"Medium","gaps":["Whether the same corepressor machinery operates at all these promoters untested"]},{"year":2013,"claim":"Uncovered a chromatin-condensation role: TRPS1 binds HDAC1/HDAC4 and boosts their activity, and its loss causes mitotic H3 hyperacetylation and prometaphase arrest; in kidney it restrains TGF-β/Smad3 to permit ureteric branching.","evidence":"Trps1 KO mouse, endogenous co-IP, HDAC activity assays, Hdac4 rescue, mitotic index; microarray and SIS3 rescue in ureteric bud culture","pmids":["23892436","23537899"],"confidence":"High","gaps":["Whether the mitotic role is transcription-independent not fully separated","Recruitment mechanism of HDACs to mitotic chromatin unclear"]},{"year":2014,"claim":"Established opposing context-dependent functions in mineralization and an angiogenic role in cancer, showing both loss and gain of TRPS1 impair dentin mineralization and that TRPS1 activates VEGFA.","evidence":"Gain/loss odontoblast cell lines with mineralization assays; ChIP for VEGFA promoter, HUVEC migration, IHC","pmids":["25128529","24595984"],"confidence":"Medium","gaps":["Switch between odontoblast maturation support and repression of mineralization genes not mechanistically defined"]},{"year":2015,"claim":"Identified nuclear cathepsin D as a non-proteolytic enhancer of TRPS1 repression on chromatin in ER+ breast cancer, linking TRPS1 to cell-cycle and anchorage-independent growth.","evidence":"Co-IP, co-localization, LexA-VP16 reporter, microarray after co-silencing, soft agar assay","pmids":["26183398"],"confidence":"Medium","gaps":["Mechanism by which non-proteolytic Cath-D enhances repression unknown"]},{"year":2016,"claim":"Showed TRPS1 suppresses EMT in cancer by directly activating FOXA1 and is repressed by miR-373, and that it activates Pde4d to drive renal tubular proliferation after injury.","evidence":"Proteomics, ChIP, knockdown/overexpression rescue, in vivo metastasis; ChIP-seq, reporter, in vivo I/R model with Pde4d/PI3K inhibition","pmids":["26969828","27466160"],"confidence":"Medium","gaps":["Determinants of FOXA1/Pde4d activation versus repression at other loci unresolved"]},{"year":2018,"claim":"Defined TRPS1's principal breast-cancer mechanism through genome-wide approaches: it represses YAP/TEAD- and ER-driven enhancers by recruiting NuRD/coREST and removing H3K27 acetylation, and is essential for tumor cell proliferation and survival.","evidence":"Genome-wide CRISPR and shRNA screens, ChIP-seq, ATAC-seq, Hi-C, mass spectrometry, knockdown phenotyping","pmids":["30082728","29895970","30380416","29471243"],"confidence":"High","gaps":["How TRPS1 is targeted specifically to YAP/ER enhancers not fully resolved","Relative contributions of NuRD versus coREST unclear"]},{"year":2019,"claim":"Demonstrated tumor-suppressor activity in mammary epithelium via interferon-signaling suppression and lactogenic differentiation, and a developmental role in zygotic genome activation through histone-mark regulation.","evidence":"Conditional mammary KO, organoid culture, RNA-seq; embryo siRNA microinjection with histone mark immunofluorescence","pmids":["31879358","30712485"],"confidence":"High","gaps":["Direct interferon-pathway target genes of TRPS1 not all defined","ZGA role rests on single-lab embryo knockdown"]},{"year":2019,"claim":"Showed TRPS1 cooperates with the Gli3 activator to directly activate Wnt5a during chondrocyte differentiation, reinforcing its dual repressor/activator capacity in skeletal development.","evidence":"ChIP and reporter assays at the Wnt5a URS1, Trps1/Gli3 double-knockout mouse analysis","pmids":["31550480"],"confidence":"Medium","gaps":["Structural basis of cooperative activation with Gli3A not defined"]},{"year":2021,"claim":"Revealed a transcription-independent oncogenic mechanism: TRPS1 reads H3K9me3 at heterochromatic replication origins via its GATA and IKAROS domains and promotes APC/C chromatin loading, driving origin refiring and genome amplification, lost in TRPS-associated mutants.","evidence":"Epigenomic decomposition, ChIP-seq, replication origin and APC/C loading assays, domain mutagenesis, tumor xenografts","pmids":["33691114"],"confidence":"High","gaps":["How TRPS1 mechanistically recruits APC/C to chromatin not detailed","Relationship between this chromatin-reader role and its corepressor role unclear"]},{"year":2021,"claim":"Extended TRPS1 transcriptional control to Leydig cell proliferation via direct regulation of Srcin1 and the Src/Akt/Ccnd1 pathway.","evidence":"ChIP-seq, ChIP-qPCR, RNA-seq, siRNA knockdown with signaling readouts","pmids":["34185441"],"confidence":"Medium","gaps":["Whether Srcin1 regulation is repressive or activating not clearly framed","Single-lab finding"]},{"year":2024,"claim":"Identified a recurrent cancer mutation (R544Q) that gains pro-metastatic function in colorectal cancer through a TRPS1-ZEB1 axis.","evidence":"Single-cell exome sequencing, in vitro and in vivo invasion/migration assays","pmids":["39307879"],"confidence":"Medium","gaps":["Mechanism by which R544Q alters TRPS1 activity not defined","Whether the mutation affects DNA binding or partner recruitment untested"]},{"year":null,"claim":"How TRPS1's molecular activity is switched between transcriptional repression, transcriptional activation, and its non-transcriptional replication-origin/APC/C function in a context-specific manner remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model explaining repressor versus activator behavior at different promoters","Targeting determinants directing TRPS1 to specific enhancers/origins undefined","How post-translational modifications (SUMOylation) and partners integrate to set activity mode unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,6,9,11,22,23,32]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,6,9,11,30]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[30]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[18]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[23,24,30]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,6,9,23,24]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[18,23,24,30]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,6,9,12,16]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[30]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[23,30,34]}],"complexes":["NuRD complex","coREST complex"],"partners":["HDAC1","HDAC4","LC8A/DYNLL1","RNF4","UBC9","GLI3","CATHEPSIN D/CTSD"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UHF7","full_name":"Zinc finger transcription factor Trps1","aliases":["Tricho-rhino-phalangeal syndrome type I protein","Zinc finger protein GC79"],"length_aa":1281,"mass_kda":141.5,"function":"Transcriptional repressor. Binds specifically to GATA sequences and represses expression of GATA-regulated genes at selected sites and stages in vertebrate development. Regulates chondrocyte proliferation and differentiation. Executes multiple functions in proliferating chondrocytes, expanding the region of distal chondrocytes, activating proliferation in columnar cells and supporting the differentiation of columnar into hypertrophic chondrocytes","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UHF7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRPS1","classification":"Not Classified","n_dependent_lines":25,"n_total_lines":1208,"dependency_fraction":0.020695364238410598},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CTBP1","stoichiometry":0.2},{"gene":"CTBP2","stoichiometry":0.2},{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2},{"gene":"HDAC1","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"RBBP4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TRPS1","total_profiled":1310},"omim":[{"mim_id":"615583","title":"VERHEIJ SYNDROME; VRJS","url":"https://www.omim.org/entry/615583"},{"mim_id":"614701","title":"CORNELIA DE LANGE SYNDROME 4 WITH OR WITHOUT MIDLINE BRAIN DEFECTS; CDLS4","url":"https://www.omim.org/entry/614701"},{"mim_id":"610187","title":"DIAPHRAGMATIC HERNIA 3; DIH3","url":"https://www.omim.org/entry/610187"},{"mim_id":"608160","title":"SRY-BOX 9; SOX9","url":"https://www.omim.org/entry/608160"},{"mim_id":"606195","title":"IROQUOIS HOMEOBOX PROTEIN 5; IRX5","url":"https://www.omim.org/entry/606195"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"breast","ntpm":56.9}],"url":"https://www.proteinatlas.org/search/TRPS1"},"hgnc":{"alias_symbol":["LGCR","GC79"],"prev_symbol":[]},"alphafold":{"accession":"Q9UHF7","domains":[{"cath_id":"-","chopping":"307-359","consensus_level":"high","plddt":76.8315,"start":307,"end":359},{"cath_id":"-","chopping":"518-581_615-631","consensus_level":"medium","plddt":69.1533,"start":518,"end":631},{"cath_id":"3.30.50.10","chopping":"894-945","consensus_level":"medium","plddt":81.624,"start":894,"end":945},{"cath_id":"-","chopping":"1215-1267","consensus_level":"high","plddt":85.5902,"start":1215,"end":1267}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHF7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHF7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHF7-F1-predicted_aligned_error_v6.png","plddt_mean":48.53},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRPS1","jax_strain_url":"https://www.jax.org/strain/search?query=TRPS1"},"sequence":{"accession":"Q9UHF7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UHF7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UHF7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHF7"}},"corpus_meta":[{"pmid":"21673316","id":"PMC_21673316","title":"TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer.","date":"2011","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21673316","citation_count":250,"is_preprint":false},{"pmid":"33011748","id":"PMC_33011748","title":"TRPS1: a highly sensitive and specific marker for breast carcinoma, especially for triple-negative breast cancer.","date":"2020","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/33011748","citation_count":161,"is_preprint":false},{"pmid":"21868360","id":"PMC_21868360","title":"miR-221/222 targeting of trichorhinophalangeal 1 (TRPS1) promotes epithelial-to-mesenchymal transition in breast cancer.","date":"2011","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21868360","citation_count":131,"is_preprint":false},{"pmid":"11285235","id":"PMC_11285235","title":"Transcriptional repression and developmental functions of the atypical vertebrate GATA protein TRPS1.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11285235","citation_count":124,"is_preprint":false},{"pmid":"17997399","id":"PMC_17997399","title":"Trps1 regulates proliferation and apoptosis of chondrocytes through Stat3 signaling.","date":"2007","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/17997399","citation_count":110,"is_preprint":false},{"pmid":"22544738","id":"PMC_22544738","title":"Control of mesenchymal lineage progression by microRNAs targeting skeletal gene regulators Trps1 and Runx2.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22544738","citation_count":97,"is_preprint":false},{"pmid":"12446778","id":"PMC_12446778","title":"Deletion of the GATA domain of TRPS1 causes an absence of facial hair and provides new insights into the bone disorder in inherited tricho-rhino-phalangeal syndromes.","date":"2002","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12446778","citation_count":94,"is_preprint":false},{"pmid":"19389374","id":"PMC_19389374","title":"Trps1, a regulator of chondrocyte proliferation and differentiation, interacts with the activator form of Gli3.","date":"2009","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/19389374","citation_count":82,"is_preprint":false},{"pmid":"30082728","id":"PMC_30082728","title":"TRPS1 shapes YAP/TEAD-dependent transcription in breast cancer cells.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30082728","citation_count":68,"is_preprint":false},{"pmid":"35413381","id":"PMC_35413381","title":"TRPS1, GATA3, and SOX10 expression in triple-negative breast carcinoma.","date":"2022","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/35413381","citation_count":65,"is_preprint":false},{"pmid":"12761050","id":"PMC_12761050","title":"Nuclear interaction of the dynein light chain LC8a with the TRPS1 transcription factor suppresses the transcriptional repression activity of TRPS1.","date":"2003","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12761050","citation_count":62,"is_preprint":false},{"pmid":"23133399","id":"PMC_23133399","title":"Trps1 and its target gene Sox9 regulate epithelial proliferation in the developing hair follicle and are associated with hypertrichosis.","date":"2012","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23133399","citation_count":61,"is_preprint":false},{"pmid":"26969828","id":"PMC_26969828","title":"Down-regulation of TRPS1 stimulates epithelial-mesenchymal transition and metastasis through repression of FOXA1.","date":"2016","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26969828","citation_count":60,"is_preprint":false},{"pmid":"14997205","id":"PMC_14997205","title":"Expression and copy number analysis of TRPS1, EIF3S3 and MYC genes in breast and prostate cancer.","date":"2004","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/14997205","citation_count":58,"is_preprint":false},{"pmid":"30380416","id":"PMC_30380416","title":"TRPS1 Is a Lineage-Specific Transcriptional Dependency in Breast Cancer.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30380416","citation_count":54,"is_preprint":false},{"pmid":"31879358","id":"PMC_31879358","title":"TRPS1 acts as a context-dependent regulator of mammary epithelial cell growth/differentiation and breast cancer development.","date":"2019","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/31879358","citation_count":53,"is_preprint":false},{"pmid":"22115758","id":"PMC_22115758","title":"Trps1 activates a network of secreted Wnt inhibitors and transcription factors crucial to vibrissa follicle morphogenesis.","date":"2011","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/22115758","citation_count":53,"is_preprint":false},{"pmid":"14560312","id":"PMC_14560312","title":"Novel missense mutations in the TRPS1 transcription factor define the nuclear localization signal.","date":"2004","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/14560312","citation_count":52,"is_preprint":false},{"pmid":"18713754","id":"PMC_18713754","title":"A position effect on TRPS1 is associated with Ambras syndrome in humans and the Koala phenotype in mice.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18713754","citation_count":51,"is_preprint":false},{"pmid":"21630221","id":"PMC_21630221","title":"The function of TRPS1 in the development and differentiation of bone, kidney, and hair follicles.","date":"2011","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/21630221","citation_count":49,"is_preprint":false},{"pmid":"25277197","id":"PMC_25277197","title":"A central role for TRPS1 in the control of cell cycle and cancer development.","date":"2014","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25277197","citation_count":48,"is_preprint":false},{"pmid":"8530105","id":"PMC_8530105","title":"A 4-megabase YAC contig that spans the Langer-Giedion syndrome region on human chromosome 8q24.1: use in refining the location of the trichorhinophalangeal syndrome and multiple exostoses genes (TRPS1 and EXT1).","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8530105","citation_count":48,"is_preprint":false},{"pmid":"35175968","id":"PMC_35175968","title":"TRPS1 Expression in Breast Carcinomas: Focusing on Metaplastic Breast Carcinomas.","date":"2022","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/35175968","citation_count":47,"is_preprint":false},{"pmid":"19820125","id":"PMC_19820125","title":"Trps1 functions downstream of Bmp7 in kidney development.","date":"2009","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/19820125","citation_count":44,"is_preprint":false},{"pmid":"32345665","id":"PMC_32345665","title":"NDRG1-PLAG1 and TRPS1-PLAG1 Fusion Genes in Chondroid Syringoma.","date":"2020","source":"Cancer genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/32345665","citation_count":44,"is_preprint":false},{"pmid":"19759027","id":"PMC_19759027","title":"Identification of the GATA factor TRPS1 as a repressor of the osteocalcin promoter.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19759027","citation_count":44,"is_preprint":false},{"pmid":"12885770","id":"PMC_12885770","title":"The RING finger protein RNF4, a co-regulator of transcription, interacts with the TRPS1 transcription factor.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12885770","citation_count":44,"is_preprint":false},{"pmid":"20507941","id":"PMC_20507941","title":"Trps1 haploinsufficiency promotes renal fibrosis by increasing Arkadia expression.","date":"2010","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/20507941","citation_count":42,"is_preprint":false},{"pmid":"18054290","id":"PMC_18054290","title":"Dynamic expression of the zinc-finger transcription factor Trps1 during hair follicle morphogenesis and cycling.","date":"2007","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/18054290","citation_count":42,"is_preprint":false},{"pmid":"21761336","id":"PMC_21761336","title":"Expression and relevance of TRPS-1: a new GATA transcription factor in breast cancer.","date":"2011","source":"Hormones & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21761336","citation_count":42,"is_preprint":false},{"pmid":"15613454","id":"PMC_15613454","title":"The TRPS1 transcription factor: androgenic regulation in prostate cancer and high expression in breast cancer.","date":"2004","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15613454","citation_count":39,"is_preprint":false},{"pmid":"18363966","id":"PMC_18363966","title":"Trps1 plays a pivotal role downstream of Gdf5 signaling in promoting chondrogenesis and apoptosis of ATDC5 cells.","date":"2008","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/18363966","citation_count":39,"is_preprint":false},{"pmid":"35063444","id":"PMC_35063444","title":"Expression of TRPS1 in phyllodes tumor and sarcoma of the breast.","date":"2022","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/35063444","citation_count":36,"is_preprint":false},{"pmid":"18456591","id":"PMC_18456591","title":"Trps1 deficiency enlarges the proliferative zone of growth plate cartilage by upregulation of Pthrp.","date":"2008","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/18456591","citation_count":36,"is_preprint":false},{"pmid":"11773701","id":"PMC_11773701","title":"Structure and function of GC79/TRPS1, a novel androgen-repressible apoptosis gene.","date":"2002","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/11773701","citation_count":35,"is_preprint":false},{"pmid":"26183398","id":"PMC_26183398","title":"Nuclear cathepsin D enhances TRPS1 transcriptional repressor function to regulate cell cycle progression and transformation in human breast cancer cells.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26183398","citation_count":34,"is_preprint":false},{"pmid":"28944451","id":"PMC_28944451","title":"Expression of miRNA-26b-5p and its target TRPS1 is associated with radiation exposure in post-Chernobyl breast cancer.","date":"2017","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28944451","citation_count":33,"is_preprint":false},{"pmid":"14516672","id":"PMC_14516672","title":"Expression of Trps1 during mouse embryonic development.","date":"2002","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/14516672","citation_count":31,"is_preprint":false},{"pmid":"29471243","id":"PMC_29471243","title":"TRPS1 Suppresses Breast Cancer Epithelial-mesenchymal Transition Program as a Negative Regulator of SUZ12.","date":"2018","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29471243","citation_count":30,"is_preprint":false},{"pmid":"36808637","id":"PMC_36808637","title":"Immunohistochemical expression of TRPS1 in mammary Paget disease, extramammary Paget disease, and their close histopathologic mimics.","date":"2023","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36808637","citation_count":29,"is_preprint":false},{"pmid":"33415005","id":"PMC_33415005","title":"Downregulation of circ-TRPS1 suppressed prostatic cancer prognoses by regulating miR-124-3p/EZH2 axis-mediated stemness.","date":"2020","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33415005","citation_count":29,"is_preprint":false},{"pmid":"29895970","id":"PMC_29895970","title":"TRPS1 regulates oestrogen receptor binding and histone acetylation at enhancers.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/29895970","citation_count":28,"is_preprint":false},{"pmid":"25128529","id":"PMC_25128529","title":"Dual role of the Trps1 transcription factor in dentin mineralization.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25128529","citation_count":27,"is_preprint":false},{"pmid":"32982402","id":"PMC_32982402","title":"LncRNA PVT1 Regulates TRPS1 Expression in Breast Cancer by Sponging miR-543.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/32982402","citation_count":25,"is_preprint":false},{"pmid":"30787327","id":"PMC_30787327","title":"TRIB1 and TRPS1 variants, G × G and G × E interactions on serum lipid levels, the risk of coronary heart disease and ischemic stroke.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30787327","citation_count":25,"is_preprint":false},{"pmid":"18442308","id":"PMC_18442308","title":"Quantitative trait loci for BMD in an SM/J by NZB/BlNJ intercross population and identification of Trps1 as a probable candidate gene.","date":"2008","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/18442308","citation_count":25,"is_preprint":false},{"pmid":"24595984","id":"PMC_24595984","title":"TRPS1 expression promotes angiogenesis and affects VEGFA expression in breast cancer.","date":"2014","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/24595984","citation_count":24,"is_preprint":false},{"pmid":"22427063","id":"PMC_22427063","title":"Trps1 is necessary for normal temporomandibular joint development.","date":"2012","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/22427063","citation_count":24,"is_preprint":false},{"pmid":"14680804","id":"PMC_14680804","title":"The atypical GATA protein TRPS1 represses androgen-induced prostate-specific antigen expression in LNCaP prostate cancer cells.","date":"2003","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/14680804","citation_count":24,"is_preprint":false},{"pmid":"33691114","id":"PMC_33691114","title":"TRPS1 drives heterochromatic origin refiring and cancer genome evolution.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33691114","citation_count":23,"is_preprint":false},{"pmid":"36284362","id":"PMC_36284362","title":"Matrix Gla protein (MGP), GATA3, and TRPS1: a novel diagnostic panel to determine breast origin.","date":"2022","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/36284362","citation_count":22,"is_preprint":false},{"pmid":"31550480","id":"PMC_31550480","title":"Wnt5a is a transcriptional target of Gli3 and Trps1 at the onset of chondrocyte hypertrophy.","date":"2019","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/31550480","citation_count":22,"is_preprint":false},{"pmid":"35863130","id":"PMC_35863130","title":"Functional mechanisms of TRPS1 in disease progression and its potential role in personalized medicine.","date":"2022","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/35863130","citation_count":21,"is_preprint":false},{"pmid":"38052269","id":"PMC_38052269","title":"TRPS1 expression in primary and metastatic prostatic adenocarcinoma, muscle invasive bladder urothelial carcinoma, and breast carcinoma: Is TRPS1 truly specific and sensitive for a breast primary?","date":"2023","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38052269","citation_count":21,"is_preprint":false},{"pmid":"24934762","id":"PMC_24934762","title":"Association of TRPS1 gene with different EMT markers in ERα-positive and ERα-negative breast cancer.","date":"2014","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24934762","citation_count":21,"is_preprint":false},{"pmid":"38647255","id":"PMC_38647255","title":"TRPS1 is a Highly Sensitive Marker for Breast Cancer: A Tissue Microarray Study Evaluating More Than 19,000 Tumors From 152 Different Tumor Entities.","date":"2024","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38647255","citation_count":20,"is_preprint":false},{"pmid":"35760555","id":"PMC_35760555","title":"Evaluation of TRPS1 Expression in Pleural Effusion Cytology Specimens With Metastatic Breast Carcinoma.","date":"2022","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/35760555","citation_count":20,"is_preprint":false},{"pmid":"23892436","id":"PMC_23892436","title":"The multi zinc-finger protein Trps1 acts as a regulator of histone deacetylation during mitosis.","date":"2013","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/23892436","citation_count":20,"is_preprint":false},{"pmid":"23451857","id":"PMC_23451857","title":"Trichorhinophalangeal syndrome with low expression of TRPS1 on epidermal and hair follicle epithelial cells.","date":"2013","source":"The Journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/23451857","citation_count":20,"is_preprint":false},{"pmid":"38000676","id":"PMC_38000676","title":"TRPS1 expression in primary and secondary extramammary Paget diseases: An immunohistochemical analysis of 93 cases.","date":"2023","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38000676","citation_count":19,"is_preprint":false},{"pmid":"30712485","id":"PMC_30712485","title":"Atypical GATA protein TRPS1 plays indispensable roles in mouse two-cell embryo.","date":"2019","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/30712485","citation_count":19,"is_preprint":false},{"pmid":"36055933","id":"PMC_36055933","title":"Utility of TRPS-1 immunohistochemistry in diagnosis of metastatic breast carcinoma in cytology specimens.","date":"2022","source":"Journal of the American Society of Cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/36055933","citation_count":19,"is_preprint":false},{"pmid":"25177352","id":"PMC_25177352","title":"A novel TRPS1 gene mutation causing trichorhinophalangeal syndrome with growth hormone responsive short stature: a case report and review of the literature.","date":"2014","source":"International journal of pediatric endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/25177352","citation_count":19,"is_preprint":false},{"pmid":"22315192","id":"PMC_22315192","title":"Third case of 8q23.3-q24.13 deletion in a patient with Langer-Giedion syndrome phenotype without TRPS1 gene deletion.","date":"2012","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/22315192","citation_count":19,"is_preprint":false},{"pmid":"39307879","id":"PMC_39307879","title":"Single-cell exome sequencing reveals polyclonal seeding and TRPS1 mutations in colon cancer metastasis.","date":"2024","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39307879","citation_count":18,"is_preprint":false},{"pmid":"36810569","id":"PMC_36810569","title":"TRPS1 Is Differentially Expressed in a Variety of Malignant and Benign Cutaneous Sweat Gland Neoplasms.","date":"2023","source":"Dermatopathology (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36810569","citation_count":18,"is_preprint":false},{"pmid":"33293831","id":"PMC_33293831","title":"TRPS1 and YAP1 Regulate Cell Proliferation and Drug Resistance of Osteosarcoma via Competitively Binding to the Target of circTADA2A - miR-129-5p.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33293831","citation_count":18,"is_preprint":false},{"pmid":"35399640","id":"PMC_35399640","title":"Paclitaxel Resistance Modulated by the Interaction between TRPS1 and AF178030.2 in Triple-Negative Breast Cancer.","date":"2022","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/35399640","citation_count":18,"is_preprint":false},{"pmid":"22508542","id":"PMC_22508542","title":"Transcriptional repression of the Dspp gene leads to dentinogenesis imperfecta phenotype in Col1a1-Trps1 transgenic mice.","date":"2012","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/22508542","citation_count":18,"is_preprint":false},{"pmid":"27466160","id":"PMC_27466160","title":"Transcription Factor Trps1 Promotes Tubular Cell Proliferation after Ischemia-Reperfusion Injury through cAMP-Specific 3',5'-Cyclic Phosphodiesterase 4D and AKT.","date":"2016","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/27466160","citation_count":17,"is_preprint":false},{"pmid":"17467349","id":"PMC_17467349","title":"Proteomic analysis of proteins regulated by TRPS1 transcription factor in DU145 prostate cancer cells.","date":"2007","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/17467349","citation_count":17,"is_preprint":false},{"pmid":"17244685","id":"PMC_17244685","title":"Concurrent transcriptional deregulation of AML1/RUNX1 and GATA factors by the AML1-TRPS1 chimeric gene in t(8;21)(q24;q22) acute myeloid leukemia.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17244685","citation_count":17,"is_preprint":false},{"pmid":"30691926","id":"PMC_30691926","title":"Trps1 transcription factor regulates mineralization of dental tissues and proliferation of tooth organ cells.","date":"2019","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/30691926","citation_count":16,"is_preprint":false},{"pmid":"37352847","id":"PMC_37352847","title":"Utility of TRPS1 immunohistochemistry in confirming breast carcinoma: Emphasis on staining in triple-negative breast cancers and gynecologic tumors.","date":"2023","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/37352847","citation_count":16,"is_preprint":false},{"pmid":"17854380","id":"PMC_17854380","title":"Missense mutation in exon 7 of TRPS1 gene in an Italian family with a mild form of trichorhinophalangeal syndrome type I.","date":"2007","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/17854380","citation_count":16,"is_preprint":false},{"pmid":"37074839","id":"PMC_37074839","title":"TRPS1 and GATA3 Expression in Invasive Breast Carcinoma With Apocrine Differentiation.","date":"2024","source":"Archives of pathology & laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37074839","citation_count":15,"is_preprint":false},{"pmid":"38389280","id":"PMC_38389280","title":"TRPS1 expression in non-melanocytic cutaneous neoplasms: an immunohistochemical analysis of 200 cases.","date":"2024","source":"Journal of pathology and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38389280","citation_count":15,"is_preprint":false},{"pmid":"31569377","id":"PMC_31569377","title":"Reciprocal Regulation of TRPS1 and miR-221 in Intervertebral Disc Cells.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31569377","citation_count":15,"is_preprint":false},{"pmid":"23537899","id":"PMC_23537899","title":"The loss of Trps1 suppresses ureteric bud branching because of the activation of TGF-β signaling.","date":"2013","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/23537899","citation_count":15,"is_preprint":false},{"pmid":"24416236","id":"PMC_24416236","title":"Trps1 differentially modulates the bone mineral density between male and female mice and its polymorphism associates with BMD differently between women and men.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24416236","citation_count":15,"is_preprint":false},{"pmid":"36162599","id":"PMC_36162599","title":"Frequent TRPS1 expression in synovial sarcoma is associated with SS18-SSX fusion oncoprotein activity.","date":"2022","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36162599","citation_count":14,"is_preprint":false},{"pmid":"32502225","id":"PMC_32502225","title":"Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32502225","citation_count":14,"is_preprint":false},{"pmid":"17391059","id":"PMC_17391059","title":"SUMOylation modulates transcriptional repression by TRPS1.","date":"2007","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17391059","citation_count":14,"is_preprint":false},{"pmid":"34216368","id":"PMC_34216368","title":"TRPS1 knockdown inhibits angiogenic vascular mimicry in human triple negative breast cancer cells.","date":"2021","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/34216368","citation_count":14,"is_preprint":false},{"pmid":"22306695","id":"PMC_22306695","title":"Genetic variation in TRPS1 may regulate hip geometry as well as bone mineral density.","date":"2012","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/22306695","citation_count":14,"is_preprint":false},{"pmid":"36971374","id":"PMC_36971374","title":"TRPS1 expression is sensitive and specific for primary extramammary Paget disease.","date":"2023","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/36971374","citation_count":13,"is_preprint":false},{"pmid":"12617849","id":"PMC_12617849","title":"Expression of Trps1 during mouse embryonic development.","date":"2002","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/12617849","citation_count":13,"is_preprint":false},{"pmid":"34185441","id":"PMC_34185441","title":"Trps1 targets Ccnd1 to regulate mouse Leydig cell proliferation.","date":"2021","source":"Andrology","url":"https://pubmed.ncbi.nlm.nih.gov/34185441","citation_count":12,"is_preprint":false},{"pmid":"32695669","id":"PMC_32695669","title":"TRPS1 Confers Multidrug Resistance of Breast Cancer Cells by Regulating BCRP Expression.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32695669","citation_count":12,"is_preprint":false},{"pmid":"37565763","id":"PMC_37565763","title":"TRPS1 immunohistochemical expression in salivary gland tumors: A pilot study.","date":"2023","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/37565763","citation_count":11,"is_preprint":false},{"pmid":"38173281","id":"PMC_38173281","title":"TRPS1 is a promising marker for all subtypes of breast cancer.","date":"2024","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/38173281","citation_count":11,"is_preprint":false},{"pmid":"37012444","id":"PMC_37012444","title":"TRPS1 expression in cytokeratin 5 expressing triple negative breast cancers, its value as a marker of breast origin.","date":"2023","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/37012444","citation_count":11,"is_preprint":false},{"pmid":"37649299","id":"PMC_37649299","title":"Transcriptional repressor GATA binding 1 (TRPS1) immunoexpression in normal skin tissues and various cutaneous tumors.","date":"2023","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/37649299","citation_count":11,"is_preprint":false},{"pmid":"33015773","id":"PMC_33015773","title":"Significance of TRPS1 in the development and clinicopathologic of hepatocellular carcinoma.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33015773","citation_count":10,"is_preprint":false},{"pmid":"27706911","id":"PMC_27706911","title":"Making extra teeth: Lessons from a TRPS1 mutation.","date":"2016","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/27706911","citation_count":10,"is_preprint":false},{"pmid":"37096814","id":"PMC_37096814","title":"TRPS1 outperforms GATA3 in pleural effusions with metastatic breast carcinoma versus mesothelioma.","date":"2023","source":"Diagnostic cytopathology","url":"https://pubmed.ncbi.nlm.nih.gov/37096814","citation_count":10,"is_preprint":false},{"pmid":"33022456","id":"PMC_33022456","title":"Trps1 transcription factor represses phosphate-induced expression of SerpinB2 in osteogenic cells.","date":"2020","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/33022456","citation_count":10,"is_preprint":false},{"pmid":"38262580","id":"PMC_38262580","title":"A Comparative Evaluation of TRPS1 and GATA3 in adenoid cystic, secretory, and acinic cell carcinomas of the breast and salivary gland.","date":"2024","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38262580","citation_count":10,"is_preprint":false},{"pmid":"34108052","id":"PMC_34108052","title":"Long non-coding RNA KCNQ1OT1 promotes cell viability and migration as well as inhibiting degradation of CHON-001 cells by regulating miR-126-5p/TRPS1 axis.","date":"2021","source":"Advances in rheumatology (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34108052","citation_count":10,"is_preprint":false},{"pmid":"21122804","id":"PMC_21122804","title":"Aberrant expression of the P2 promoter-specific transcript Runx1 in epiphyseal cartilage of Trps1-null mice.","date":"2010","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21122804","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52909,"output_tokens":10648,"usd":0.159223,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21245,"output_tokens":6700,"usd":0.136862,"stage2_stop_reason":"end_turn"},"total_usd":0.296085,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"TRPS1 is a nuclear protein that binds GATA sequences but represses (rather than activates) transcription mediated by other GATA factors. Repression does not occur through competition for DNA binding but depends on a C-terminal region related to repressive domains found in Ikaros proteins. Truncating mutations identified in TRPS patients encode dominant inhibitors of wild-type TRPS1 function.\",\n      \"method\": \"Nuclear localization studies, GATA-dependent reporter assays, domain deletion analysis, transactivation assays in mammalian cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (reporter assays, DNA-binding assays, domain mutagenesis) in a foundational paper; replicated by subsequent work\",\n      \"pmids\": [\"11285235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Deletion of the GATA-type zinc finger domain of TRPS1 in mice causes absence of vibrissae, facial anomalies, thoracic skeletal defects, and generalized bone dysplasia, directly implicating the GATA zinc finger in bone and hair development.\",\n      \"method\": \"Conditional knock-in mouse model (TRPS1 GATA domain deletion), histological and skeletal analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic loss-of-function mouse model with specific skeletal and hair phenotypes, replicated in multiple mouse studies\",\n      \"pmids\": [\"12446778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The dynein light chain LC8a physically interacts with two distinct regions of TRPS1 (residues 635-723 and 1182-1281) and co-localizes with TRPS1 in dot-like nuclear structures. LC8a interaction reduces TRPS1 binding to the GATA consensus sequence (EMSA) and suppresses TRPS1-mediated transcriptional repression in reporter assays.\",\n      \"method\": \"Co-immunoprecipitation, EMSA, luciferase reporter assay, confocal microscopy\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and EMSA in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12761050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RING finger protein RNF4 interacts with TRPS1 (binding region in TRPS1 amino acids 985-1184) via yeast two-hybrid and co-immunoprecipitation from both transfected and native mammalian cells. RNF4 co-localizes with TRPS1 in distinct nuclear structures. RNF4 overexpression inhibits TRPS1 transcriptional repression activity in luciferase reporter assays.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, luciferase reporter assay, confocal laser-scanning microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus reciprocal co-IP from native cells, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"12885770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TRPS1 overexpression in androgen-dependent LNCaP prostate cancer cells inhibits transcription of a PSA enhancer/promoter-driven luciferase reporter and reduces androgen-induced endogenous PSA secretion. TRPS1 binds to an inverse GATA motif overlapping ARE III in the PSA enhancer.\",\n      \"method\": \"Luciferase reporter assay, PSA ELISA from conditioned medium, GATA motif analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter plus endogenous protein measurement, single lab\",\n      \"pmids\": [\"14680804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Two missense mutations in the RRRTRKR motif of TRPS1 (arginine to histidine or cysteine) prevent nuclear translocation of the mutant protein when expressed in COS7 cells, identifying RRRTRKR as the functional nuclear localization signal of TRPS1.\",\n      \"method\": \"Subcellular localization studies of mutant TRPS1 constructs in COS7 cells, patient mutation identification\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with mutagenesis in cell-based system, single lab\",\n      \"pmids\": [\"14560312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Trps1 directly represses Stat3 expression by binding to GATA-binding sites in the Stat3 gene promoter. In Trps1-deficient chondrocytes, elevated Stat3 drives increased cyclin D1 and Bcl2, causing diminished proliferation and decreased apoptosis. siRNA-mediated Stat3 depletion in Trps1-deficient chondrocytes normalizes cyclin D1 and Bcl2 levels. Mutation of GATA-binding sites in the Stat3 promoter abrogates Trps1 binding and repression.\",\n      \"method\": \"Trps1 knockout mouse, siRNA knockdown of Stat3, Trps1 overexpression in ATDC5 cells, mutational analysis of GATA-binding sites in Stat3 promoter, ChIP, Western blot\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including promoter mutagenesis, ChIP, rescue experiments, and genetic KO\",\n      \"pmids\": [\"17997399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TRPS1 is SUMOylated at multiple sites in vivo and in vitro through interaction with UBC9. SUMOylation at the C-terminal repression domain (primarily K1201/S5, secondarily K1192/S4) is required for TRPS1-mediated transcriptional repression; mutation of both S4 and S5 almost completely abolishes repressive activity.\",\n      \"method\": \"In vitro and in vivo SUMOylation assays, site-directed mutagenesis of SUMO acceptor sites, luciferase reporter assays, UBC9 overexpression\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of SUMOylation plus mutagenesis and functional reporter assays, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17391059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Trps1 interacts specifically with the transactivation domain of Gli3 activator form (Gli3A) but not the repressor form, both in vitro and in vivo. A 185 aa region of Trps1 containing three predicted zinc fingers is sufficient for this interaction. Genetic analysis using mouse models indicates Trps1 and Gli3 repressor activity cooperate in distal chondrocytes and have activating functions in columnar proliferating chondrocytes.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation in vivo, domain mapping with truncated constructs, mouse genetic models (double mutants)\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro binding plus in vivo co-IP plus genetic epistasis in multiple mouse models\",\n      \"pmids\": [\"19389374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Trps1 directly binds the PTHrP promoter and suppresses PTHrP transcription. Loss of Trps1 leads to expanded PTHrP expression in the growth plate and elongated proliferative zones, demonstrating that Trps1 directly represses PTHrP to regulate chondrocyte organization.\",\n      \"method\": \"ChIP assay, promoter luciferase assay, quantitative RT-PCR, Trps1 knockout mouse, tibial organ culture\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP plus reporter plus KO mouse with in vivo rescue, single lab, multiple methods\",\n      \"pmids\": [\"18456591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GDF5 induces Trps1 protein upregulation and nuclear translocation via p38 MAPK signaling downstream of ALK6 in ATDC5 chondrocytes. Trps1 acts downstream of GDF5 signaling to promote chondrogenic differentiation and apoptosis; effects are blocked by dominant-negative ALK6 or p38 MAPK inhibitor SB203580.\",\n      \"method\": \"Treatment with GDF5, dominant-negative ALK6 overexpression, SB203580 inhibitor, Western blot, immunofluorescence, differentiation assays, apoptosis assays\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic inhibition with multiple readouts, single lab\",\n      \"pmids\": [\"18363966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TRPS1 directly binds the osteocalcin promoter through a GATA binding sequence and represses osteocalcin transcription. Mutation of the GATA binding site in the mouse or human osteocalcin promoter abrogates TRPS1 binding. TRPS1 regulates osteocalcin expression in osteosarcoma cells and primary bone marrow stromal cells, and modulates mineralized bone matrix formation.\",\n      \"method\": \"Proteomic identification of TRPS1 at OSE2 sequence, EMSA, reporter assays, promoter mutagenesis, ChIP, siRNA knockdown, mineralization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — proteomic identification, EMSA with mutagenesis, ChIP, and functional mineralization assay, multiple methods in single study\",\n      \"pmids\": [\"19759027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Trps1 functions downstream of BMP7 in kidney development. BMP7-deficient kidneys show virtual absence of Trps1 expression. BMP7 induces Trps1 and E-cadherin expression and downregulates vimentin in metanephric mesenchymal cells. siRNA knockdown of Trps1 inhibits BMP7-induced mesenchymal-to-epithelial transition.\",\n      \"method\": \"Trps1 knockout mouse, Bmp7 knockout mouse analysis, in vitro metanephric mesenchymal cell culture with BMP7 treatment, siRNA knockdown, immunofluorescence, in situ hybridization\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (Bmp7 KO reduces Trps1) plus siRNA rescue in cell culture, replicated across KO models\",\n      \"pmids\": [\"19820125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Trps1 haploinsufficiency promotes TGF-β1-induced EMT and tubulointerstitial fibrosis. Trps1+/- cells have elevated Arkadia (an E3 ubiquitin ligase), increased Smad3 phosphorylation, and decreased Smad7 protein. Arkadia knockdown inhibits TGF-β1-induced EMT in Trps1+/- cells, placing Trps1 upstream of Arkadia-mediated Smad7 degradation.\",\n      \"method\": \"Trps1 heterozygous knockout mouse, unilateral ureteral obstruction model, siRNA knockdown of Arkadia, immunohistochemistry, Western blot, primary tubular cell culture\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model plus siRNA rescue, single lab, multiple orthogonal assays\",\n      \"pmids\": [\"20507941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"miR-221/222 target the 3'UTR of TRPS1 to reduce its expression, and TRPS1 inhibits EMT by directly repressing ZEB2 expression. Knockdown of TRPS1 mimics miR-221/222-induced EMT, and TRPS1 overexpression rescues the EMT phenotype. FOSL1/Fra-1 drives miR-221/222 transcription downstream of the RAS/MEK pathway.\",\n      \"method\": \"3'UTR luciferase reporter assay, TRPS1 knockdown/overexpression, qRT-PCR, migration/invasion assays, Western blot\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — 3'UTR reporter assay confirming direct targeting, knockdown/OE rescue experiments, two papers from same group corroborating findings\",\n      \"pmids\": [\"21673316\", \"21868360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Trps1 can directly bind the promoters of its target genes in the developing vibrissa follicle to activate transcription (of Wnt inhibitors and transcription factors), in addition to its established role as a transcriptional repressor. Trps1 regulates the Wnt signaling pathway in early hair follicle progenitors.\",\n      \"method\": \"Microarray hybridization, ChIP on vibrissa follicle tissue, in vivo target gene expression validation in Trps1 GATA domain deletion mice\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus microarray plus in vivo gene expression validation, single lab\",\n      \"pmids\": [\"22115758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Trps1 directly represses Sox9 expression in the developing hair follicle, as demonstrated by ChIP showing Trps1 occupancy at the Sox9 promoter and functional assays showing that Trps1 loss leads to elevated Sox9 and increased epithelial proliferation.\",\n      \"method\": \"ChIP, Trps1 GATA domain deletion mouse model (Trps1Δgt), immunofluorescence, proliferation assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus genetic KO model, single lab\",\n      \"pmids\": [\"23133399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Seven RUNX2-targeting miRNAs (miR-23a, miR-30c, miR-34c, miR-133a, miR-135a, miR-205, miR-217) also target TRPS1 through its 3'UTR, effectively blocking maturation of osteoblasts and chondrocytes and redirecting mesenchymal stem cells toward adipogenic fate.\",\n      \"method\": \"3'UTR reporter assays, miRNA overexpression in osteoblasts and chondrocytes, cell differentiation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'UTR reporter assays plus differentiation phenotype, single lab\",\n      \"pmids\": [\"22544738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Trps1 interacts with histone deacetylases Hdac1 and Hdac4, increasing their activity. Loss of Trps1 results in histone H3 hyperacetylation maintained during mitosis, impairing chromatin condensation and HP1 binding, leading to prometaphase arrest. Overexpression of Hdac4 rescues the mitotic defect in Trps1-deficient chondrocytes.\",\n      \"method\": \"Trps1 knockout mouse, co-immunoprecipitation (Trps1-Hdac1/Hdac4), HDAC activity assays, histone acetylation Western blot, mitotic index analysis, Hdac4 overexpression rescue\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP of endogenous complex, HDAC activity assay, genetic rescue experiment, multiple orthogonal readouts\",\n      \"pmids\": [\"23892436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of Trps1 suppresses ureteric bud branching through activation of TGF-β/Smad3 signaling, including upregulation of Rb1cc1 and Arkadia, increased Smad3 phosphorylation, and decreased Smad7 and c-Ski. Addition of Smad3 inhibitor SIS3 restores branching in Trps1-deficient ureteric buds in organ culture.\",\n      \"method\": \"Trps1 knockout mouse, DNA microarray of cultured ureteric buds, Western blot, immunohistochemistry, TUNEL, PCNA staining, SIS3 inhibitor rescue in organ culture\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus pharmacological rescue in organ culture, single lab, multiple methods\",\n      \"pmids\": [\"23537899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Trps1 serves dual context-dependent functions in dentin mineralization: Trps1 is required for odontoblast maturation (supports expression of Alpl and Phospho1 needed to initiate mineralization), while in mature odontoblasts Trps1 represses mineralization-related genes (downregulates phosphate homeostasis genes). Both loss and overexpression of Trps1 impair mineralization.\",\n      \"method\": \"Stable Trps1-deficient and Trps1-overexpressing odontoblastic cell lines, alkaline phosphatase staining, alizarin red staining, qRT-PCR of target genes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable cell lines with gain and loss of function, multiple mineralization assays, single lab\",\n      \"pmids\": [\"25128529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nuclear cathepsin D (Cath-D) interacts with TRPS1 and they co-localize in the nucleus of ER+ breast cancer cells where both are associated with chromatin. Cath-D enhances TRPS1-mediated transcriptional repression (including of PTHrP) in a non-proteolytic manner. BAT3 controls Cath-D nuclear targeting. Co-silencing of Cath-D and TRPS1 impairs cell cycle progression and soft agar colony formation.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by microscopy, LexA-VP16 reporter assay, microarray after Cath-D/TRPS1 silencing, siRNA knockdown, soft agar assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus reporter assay plus functional knockdown, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26183398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRPS1 acts as a transcriptional activator of FOXA1 by directly binding the FOXA1 promoter, thereby suppressing EMT. TRPS1 knockdown decreases FOXA1 expression and promotes EMT, migration, invasion, and in vivo metastasis; ectopic FOXA1 expression blocks EMT enhancement caused by TRPS1 silencing. miR-373 binding to the TRPS1 3'UTR reduces TRPS1 expression.\",\n      \"method\": \"Quantitative proteomics, ChIP, TRPS1 knockdown/overexpression, FOXA1 overexpression rescue, invasion/migration assays, in vivo metastasis model, luciferase 3'UTR assay\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding plus proteomic identification plus functional rescue, single lab\",\n      \"pmids\": [\"26969828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRPS1 is a potent repressor of YAP/TEAD-dependent transcription in breast cancer. TRPS1 binds a large set of joint genomic enhancers with YAP and recruits corepressor complexes, reducing H3K27 acetylation. Loss of TRPS1 (identified by genome-wide CRISPR screen) leads to enhancer activation, altered promoter-enhancer interaction landscape, and increased YAP-dependent transcription.\",\n      \"method\": \"Genome-wide CRISPR screen, ChIP-seq, ATAC-seq, H3K27ac ChIP-seq, Hi-C/promoter-enhancer interaction analysis, TRPS1 knockout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genome-wide CRISPR screen plus multi-omics (ChIP-seq, ATAC-seq, Hi-C) in single comprehensive study\",\n      \"pmids\": [\"30082728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRPS1 associates with the NuRD and coREST histone deacetylation complexes (identified by proteomic and genomic approaches). TRPS1 is required for repressing spurious ER binding and removing histone acetylation at cis-regulatory elements in breast cancer cells, thereby regulating cell proliferation.\",\n      \"method\": \"Focused siRNA screen (330 chromatin regulators), proteomics (mass spectrometry), ChIP-seq for ER and TRPS1, H3K27ac ChIP-seq, TRPS1 knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — proteomic identification of complex plus ChIP-seq genomic validation plus functional phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"29895970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRPS1 knockdown results in perturbed mitosis, apoptosis, and reduced tumor growth in breast cancer cells. Integrated analysis reveals TRPS1 associates with the NuRD repressor complex and regulates a transcriptional network essential for breast cancer cell survival.\",\n      \"method\": \"Targeted shRNA screen across 59 cell lines, TRPS1 knockdown, cell cycle/apoptosis assays, transcriptional target analysis, chromatin binding assays, protein interaction studies\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA screen plus chromatin binding plus protein interaction, single lab\",\n      \"pmids\": [\"30380416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRPS1 directly inhibits SUZ12 transcription by binding to the SUZ12 promoter (demonstrated by ChIP). Loss of TRPS1 results in increased SUZ12 binding and H3K27 tri-methylation at the CDH1 (E-cadherin) promoter, thereby repressing E-cadherin and promoting EMT.\",\n      \"method\": \"ChIP assay for TRPS1 at SUZ12 promoter, H3K27me3 ChIP at CDH1 promoter, TRPS1 knockdown/overexpression, Western blot, migration assays\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus epigenetic readout, single lab\",\n      \"pmids\": [\"29471243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRPS1 mediates suppression of interferon signaling to promote mammary epithelial proliferation and lactogenic differentiation. TRPS1 loss combined with E-cadherin inactivation causes persistent proliferation of mammary organoids and accelerates mammary tumor formation in mice, demonstrating context-dependent tumor suppressor activity.\",\n      \"method\": \"In vitro and in vivo Trps1 loss-of-function, mammary organoid culture, conditional mouse knockout models, RNA-seq for interferon pathway genes\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vitro and in vivo loss-of-function models with defined molecular pathway (interferon signaling) and phenotypic rescue\",\n      \"pmids\": [\"31879358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Trps1 and the Gli3 activator form cooperate to activate Wnt5a expression by binding to an upstream regulatory sequence (URS1) in the Wnt5a promoter, as shown by ChIP and reporter assays. Loss of both Trps1 and Gli3 decreases endogenous Wnt5a mRNA and protein during chondrocyte differentiation.\",\n      \"method\": \"ChIP, reporter gene assays, Trps1/Gli3 double knockout mouse analysis, Wnt5a mRNA/protein measurement\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter plus genetic epistasis, single lab\",\n      \"pmids\": [\"31550480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRPS1 is an important factor for zygotic genome activation during mouse preimplantation development. TRPS1 protein peaks at the two/four-cell stage; Trps1 knockdown reduces developmental rate (~30%), increases ZGA marker genes (MuERV-L, Zscan4d) and decreases H3K4me3 and H3K27me3 histone marks, suggesting TRPS1 normally suppresses ZGA markers through epigenetic regulation.\",\n      \"method\": \"Trps1 siRNA microinjection into mouse embryos, qRT-PCR of ZGA markers, immunofluorescence for histone marks, embryo developmental rate analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct siRNA knockdown in embryos with histone mark analysis, single lab\",\n      \"pmids\": [\"30712485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRPS1 promotes breast carcinogenesis by regulating DNA replication. TRPS1 occupies H3K9me3-marked heterochromatic replication origins and promotes chromatin loading of APC/C, resulting in uncontrolled origin refiring. TRPS1 reads H3K9me3 through its GATA and IKAROS domains. TRPS-related mutations reduce chromatin binding, replication boosting, and tumorigenicity. Overexpression of wild-type but not TRPS-associated mutant TRPS1 drives cancer genome amplifications.\",\n      \"method\": \"Epigenomic decomposition/ChIP-seq, replication origin analysis, APC/C chromatin loading assay, mutagenesis of GATA/IKAROS domains, overexpression studies, tumor xenograft models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal genomic and functional approaches, domain mutagenesis, in vivo tumor model\",\n      \"pmids\": [\"33691114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Overexpression of TRPS1 in DU145 prostate cancer cells decreases expression of antioxidant proteins (superoxide dismutase, protein disulfide isomerase A3, endoplasmin, annexin A2), mitochondria-associated proteins, glycolytic enzymes, and apoptosis-related proteins, suggesting TRPS1 involvement in oxidative stress response.\",\n      \"method\": \"2D electrophoresis, mass spectrometry of stably inducible TRPS1-expressing DU145 cells vs parental cells\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proteomics without functional validation, single lab, no mechanistic follow-up\",\n      \"pmids\": [\"17467349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Trps1 directly binds the P2 promoter of Runx1 via its GATA domain and represses Runx1 expression in growth plate chondrocytes, as demonstrated by luciferase reporter assay and ChIP. Runx1 is aberrantly expressed in Trps1-null mouse growth plate cartilage.\",\n      \"method\": \"DNA array (ATDC5 cells), luciferase promoter assay, ChIP, in situ hybridization in Trps1-null mice\",\n      \"journal\": \"Experimental and molecular pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter plus in vivo validation in KO mouse, single lab\",\n      \"pmids\": [\"21122804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TRPS1 mRNA and protein expression in androgen-dependent prostate cancer cells is down-regulated by androgens via the androgen receptor (AR), as demonstrated by androgen withdrawal/castration experiments in prostate cancer xenografts where castration increases TRPS1 protein.\",\n      \"method\": \"Androgen withdrawal (castration) in xenograft models, quantitative RT-PCR, Western blot/IHC in xenograft tissue\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo hormonal manipulation with protein-level readout, single lab\",\n      \"pmids\": [\"15613454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TRPS1 forms an AML1-TRPS1 fusion protein in a t(8;21)(q24;q22) leukemia that represses AML1 and GATA-1 transcriptional activity by two mechanisms: competition at cognate DNA-binding sites and physical sequestration of AML1 and GATA-1. The fusion stimulates proliferation of hematopoietic colony-forming cells.\",\n      \"method\": \"Identification of chimeric gene by molecular cloning, luciferase reporter assay for AML1 and GATA-1 activity, co-immunoprecipitation for physical interaction, hematopoietic colony-forming assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus co-IP plus functional colony assay, single case but multiple methods\",\n      \"pmids\": [\"17244685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Transcriptional repression of Dspp by Trps1 is the molecular basis for dentinogenesis imperfecta in Col1a1-Trps1 transgenic mice. Sustained high Trps1 levels in odontoblasts directly inhibit the Dspp promoter, reducing DSP and DPP protein levels and impairing dentin mineralization.\",\n      \"method\": \"Col1a1-Trps1 transgenic mouse, ChIP (Trps1 at Dspp promoter), micro-CT, histology, biochemical analysis of dentin matrix proteins\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus transgenic mouse plus biochemical validation, single lab\",\n      \"pmids\": [\"22508542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Trps1 directly activates Pde4d transcription by binding to its regulatory elements (shown by ChIP-seq and dual luciferase assay). Trps1 promotes renal tubular epithelial cell proliferation after ischemia-reperfusion injury through the Pde4d/PI3K/AKT signaling pathway; Pde4d knockdown or PI3K inhibition abolishes Trps1-induced proliferation.\",\n      \"method\": \"ChIP-seq, dual luciferase assay, Trps1 knockdown/overexpression in rats, Pde4d siRNA, wortmannin (PI3K inhibitor), in vivo renal I/R model\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus reporter plus in vivo pharmacological rescue, single lab\",\n      \"pmids\": [\"27466160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRPS1 promotes angiogenesis in breast cancer by directly binding the VEGFA promoter (demonstrated by ChIP) to activate VEGFA expression; TRPS1 overexpression increases HUVEC migration and VEGFA levels, while knockdown decreases both.\",\n      \"method\": \"ChIP assay for TRPS1 at VEGFA promoter, TRPS1 overexpression/knockdown, HUVEC migration assay, VEGFA qRT-PCR, immunohistochemistry for CD31/MVD\",\n      \"journal\": \"Experimental biology and medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional angiogenesis assay, single lab\",\n      \"pmids\": [\"24595984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRPS1 R544Q mutation (enriched in liver metastases of colon cancer) significantly increases CRC invasion and migration in vitro and in vivo through a TRPS1R544Q/ZEB1 axis.\",\n      \"method\": \"Single-cell exome sequencing, functional in vitro invasion/migration assays, in vivo xenograft, identification of TRPS1-ZEB1 axis\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single-cell sequencing plus functional validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"39307879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Trps1 regulates Leydig cell proliferation by binding the Srcin1 promoter to regulate its transcription, influencing Src phosphorylation levels, and thereby controlling the Src/Akt/Ccnd1 signaling pathway. Trps1 knockdown suppresses Src and Akt phosphorylation and Ccnd1 expression.\",\n      \"method\": \"ChIP-seq, ChIP-qPCR for Trps1 at Srcin1 promoter, RNA-seq, Trps1 siRNA knockdown in Leydig cells, Western blot\",\n      \"journal\": \"Andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus RNA-seq plus knockdown with signaling readout, single lab\",\n      \"pmids\": [\"34185441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRPS1 regulates BCRP (breast cancer resistance protein) expression; TRPS1 overexpression upregulates BCRP while knockdown decreases BCRP, conferring multidrug resistance of breast cancer cells.\",\n      \"method\": \"TRPS1 overexpression/knockdown, Western blot for BCRP, MTT drug sensitivity assay, immunohistochemistry in 180 breast cancer samples\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression/knockdown with Western blot, no direct promoter binding assay, single lab\",\n      \"pmids\": [\"32695669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRPS1 directly represses SerpinB2 expression in osteogenic cells by occupying regulatory elements in the SerpinB2 gene; Trps1 occupancy changes in response to inorganic phosphate (Pi). Transgenic Trps1 overexpression (2.3Col1a1-Trps1) decreases SerpinB2 in osteoblasts and odontoblasts in vivo.\",\n      \"method\": \"ChIP assay for Trps1 at SerpinB2 regulatory elements, Trps1 overexpressing cell lines, 2.3Col1a1-Trps1 transgenic mice, Western blot, mineralization assay\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus transgenic mouse validation, single lab\",\n      \"pmids\": [\"33022456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRPS1 expression in synovial sarcoma is driven at least in part by the SS18-SSX fusion oncoprotein; ChIP-seq shows enrichment of SS18-SSX at the TRPS1 locus with co-localization of RNA pol II and active histone marks, and repression of SS18::SSX in synovial sarcoma cell lines reduces TRPS1 transcript levels.\",\n      \"method\": \"Immunohistochemistry on 165 synovial sarcoma cases, publicly available gene expression datasets, ChIP-seq data analysis, SS18::SSX knockdown cell line data\",\n      \"journal\": \"Human pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — bioinformatics/public ChIP-seq reanalysis plus publicly available knockdown data, not performed de novo in this study\",\n      \"pmids\": [\"36162599\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRPS1 is an atypical GATA-type transcription factor that primarily acts as a transcriptional repressor by binding GATA consensus sequences and recruiting corepressor complexes (NuRD, coREST) and histone deacetylases (HDAC1, HDAC4); it is SUMOylated at its C-terminal Ikaros-like repression domain to enhance repression, interacts with partners including RNF4, LC8a, and cathepsin D that modulate its activity, and regulates diverse downstream targets (Stat3, PTHrP, Sox9, ZEB2, FOXA1, SUZ12, Runx1, osteocalcin, VEGFA, Dspp, Pde4d) in a context-dependent manner — functioning as a repressor in chondrogenesis, bone, and hair follicle development and as either a repressor or activator in cancer and kidney contexts — while also occupying heterochromatic replication origins to promote APC/C chromatin loading and control DNA replication fidelity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRPS1 is an atypical GATA-type transcription factor that functions predominantly as a transcriptional repressor governing cell differentiation in skeletal, hair follicle, kidney, and mammary tissues, and is co-opted in cancer [#0, #1, #23]. It binds GATA consensus sequences through its zinc finger domain but, unlike canonical GATA factors, represses transcription via a C-terminal Ikaros-related domain rather than by competing for DNA occupancy; truncating patient mutations encode dominant inhibitors of wild-type function [#0]. Repression is enforced through recruitment of the NuRD and coREST corepressor complexes and the histone deacetylases HDAC1 and HDAC4, lowering histone acetylation at target cis-regulatory elements [#18, #24]. Repressive activity is enhanced by SUMOylation of the C-terminal domain via UBC9 [#7] and modulated by partners that antagonize DNA binding (the dynein light chain LC8a and RNF4) [#2, #3] or potentiate repression (nuclear cathepsin D) [#21]. In chondrogenesis and skeletal development TRPS1 directly represses Stat3, PTHrP, Sox9, Runx1, and osteocalcin to control chondrocyte proliferation, organization, and bone mineralization, while cooperating with the Gli3 activator to regulate Wnt5a [#6, #9, #16, #11, #32, #28]; deletion of its GATA zinc finger in mice causes bone dysplasia and loss of vibrissae [#1]. In epithelial and cancer contexts TRPS1 suppresses EMT by repressing ZEB2 and SUZ12 and activating FOXA1, and acts as a potent repressor of YAP/TEAD- and ER-driven transcription required for breast cancer cell proliferation and survival [#14, #26, #22, #23, #24]. TRPS1 also promotes breast carcinogenesis through a non-transcriptional chromatin role: it reads H3K9me3 at heterochromatic replication origins via its GATA and IKAROS domains and drives APC/C chromatin loading, causing origin refiring and genome amplification, an activity lost in TRPS-associated mutants [#30]. Beyond these roles, TRPS1 regulates DNA replication fidelity and mitotic chromatin condensation, the latter through HDAC-dependent control of histone acetylation [#18, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the foundational paradox that TRPS1, despite binding GATA elements, is a transcriptional repressor acting through an Ikaros-like C-terminal domain rather than DNA-binding competition, and that patient truncations act as dominant inhibitors.\",\n      \"evidence\": \"Nuclear localization, GATA reporter and DNA-binding assays, domain deletion in mammalian cells\",\n      \"pmids\": [\"11285235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the corepressor machinery recruited by the Ikaros-like domain\", \"Direct genomic targets unknown at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Genetically linked the GATA zinc finger domain to TRPS1's developmental function, showing it is required for bone and hair follicle morphogenesis.\",\n      \"evidence\": \"Conditional GATA-domain deletion knock-in mouse with skeletal and vibrissae phenotyping\",\n      \"pmids\": [\"12446778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the direct target genes responsible for the phenotypes\", \"Mechanism of repression at target loci unaddressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified the first physical partners (LC8a, RNF4) that antagonize TRPS1 DNA binding and repression, indicating its activity is post-translationally tunable.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP from native cells, EMSA, reporter assays, confocal microscopy\",\n      \"pmids\": [\"12761050\", \"12885770\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological contexts where these interactions operate not established\", \"Whether RNF4 modifies TRPS1 enzymatically not resolved here\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapped the functional nuclear localization signal (RRRTRKR), connecting patient mutations to a defect in nuclear import.\",\n      \"evidence\": \"Subcellular localization of mutant constructs in COS7 cells with patient mutation analysis\",\n      \"pmids\": [\"14560312\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Import receptor mediating NLS recognition not identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined TRPS1's mechanism in chondrocytes by showing direct repression of Stat3 controls proliferation and apoptosis via cyclin D1 and Bcl2.\",\n      \"evidence\": \"Trps1 KO mouse, ChIP, promoter GATA-site mutagenesis, Stat3 siRNA rescue in chondrocytes\",\n      \"pmids\": [\"17997399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Corepressor complex at the Stat3 promoter not defined\", \"Generality to other tissues untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed SUMOylation of the C-terminal repression domain via UBC9 is required for full repressive activity, revealing post-translational control of TRPS1 function.\",\n      \"evidence\": \"In vitro and in vivo SUMOylation assays, acceptor-site mutagenesis, reporter assays\",\n      \"pmids\": [\"17391059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SUMOylation mechanistically enhances corepressor recruitment not shown\", \"Desumoylation regulation unaddressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connected TRPS1 to hormonal and oncogenic contexts: androgen/AR downregulates TRPS1 in prostate cancer, an AML1-TRPS1 fusion sequesters AML1/GATA-1 in leukemia, and TRPS1 alters oxidative-stress proteomes.\",\n      \"evidence\": \"Castration xenograft, molecular cloning of fusion, reporter and colony assays, 2D-MS proteomics\",\n      \"pmids\": [\"15613454\", \"17244685\", \"17467349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Oxidative-stress proteome finding (idx 31) is Low-confidence and lacks functional validation\", \"Fusion derived from single leukemia case\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed TRPS1's context-dependent activator role and skeletal target network: it interacts with the Gli3 activator and directly represses PTHrP, while GDF5/p38 MAPK signaling drives its nuclear accumulation.\",\n      \"evidence\": \"Co-IP, domain mapping, double-mutant mouse genetics, ChIP, promoter reporters, pharmacological inhibition in ATDC5 cells\",\n      \"pmids\": [\"19389374\", \"18456591\", \"18363966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular switch between Gli3 cooperative activation and repression not defined\", \"Direct Gli3-binding interface incompletely mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended the skeletal target repertoire (osteocalcin) and placed TRPS1 downstream of BMP7 in kidney mesenchymal-to-epithelial transition.\",\n      \"evidence\": \"EMSA, ChIP, promoter mutagenesis, mineralization assays, Bmp7/Trps1 KO mice, siRNA rescue\",\n      \"pmids\": [\"19759027\", \"19820125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How BMP7 induces Trps1 transcriptionally not resolved\", \"Direct kidney target genes not all defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed TRPS1 dosage controls TGF-\\u03b2/Smad signaling in kidney fibrosis through Arkadia-mediated Smad7 degradation, and identified Runx1 as a direct repression target.\",\n      \"evidence\": \"Trps1+/- mouse, ureteral obstruction model, Arkadia siRNA rescue, ChIP and reporter for Runx1 P2 promoter\",\n      \"pmids\": [\"20507941\", \"21122804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Arkadia is a direct or indirect Trps1 target unclear\", \"Single-lab observations for the fibrosis axis\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated TRPS1 can directly activate transcription in hair follicle progenitors and is itself an EMT-suppressing target of miR-221/222 acting through ZEB2 repression.\",\n      \"evidence\": \"ChIP plus microarray in vibrissa follicle, GATA-deletion mice, 3'UTR luciferase reporter, knockdown/overexpression rescue\",\n      \"pmids\": [\"22115758\", \"21673316\", \"21868360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of activator versus repressor behavior at a given promoter not defined\", \"Cofactors enabling activation not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Broadened the developmental target network (Sox9 in hair follicle; Dspp in dentin) and showed multiple RUNX2-targeting miRNAs converge on the TRPS1 3'UTR to control mesenchymal cell fate.\",\n      \"evidence\": \"ChIP, GATA-deletion and Col1a1-Trps1 transgenic mice, 3'UTR reporters, differentiation assays\",\n      \"pmids\": [\"23133399\", \"22508542\", \"22544738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the same corepressor machinery operates at all these promoters untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Uncovered a chromatin-condensation role: TRPS1 binds HDAC1/HDAC4 and boosts their activity, and its loss causes mitotic H3 hyperacetylation and prometaphase arrest; in kidney it restrains TGF-\\u03b2/Smad3 to permit ureteric branching.\",\n      \"evidence\": \"Trps1 KO mouse, endogenous co-IP, HDAC activity assays, Hdac4 rescue, mitotic index; microarray and SIS3 rescue in ureteric bud culture\",\n      \"pmids\": [\"23892436\", \"23537899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the mitotic role is transcription-independent not fully separated\", \"Recruitment mechanism of HDACs to mitotic chromatin unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established opposing context-dependent functions in mineralization and an angiogenic role in cancer, showing both loss and gain of TRPS1 impair dentin mineralization and that TRPS1 activates VEGFA.\",\n      \"evidence\": \"Gain/loss odontoblast cell lines with mineralization assays; ChIP for VEGFA promoter, HUVEC migration, IHC\",\n      \"pmids\": [\"25128529\", \"24595984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Switch between odontoblast maturation support and repression of mineralization genes not mechanistically defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified nuclear cathepsin D as a non-proteolytic enhancer of TRPS1 repression on chromatin in ER+ breast cancer, linking TRPS1 to cell-cycle and anchorage-independent growth.\",\n      \"evidence\": \"Co-IP, co-localization, LexA-VP16 reporter, microarray after co-silencing, soft agar assay\",\n      \"pmids\": [\"26183398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which non-proteolytic Cath-D enhances repression unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed TRPS1 suppresses EMT in cancer by directly activating FOXA1 and is repressed by miR-373, and that it activates Pde4d to drive renal tubular proliferation after injury.\",\n      \"evidence\": \"Proteomics, ChIP, knockdown/overexpression rescue, in vivo metastasis; ChIP-seq, reporter, in vivo I/R model with Pde4d/PI3K inhibition\",\n      \"pmids\": [\"26969828\", \"27466160\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of FOXA1/Pde4d activation versus repression at other loci unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined TRPS1's principal breast-cancer mechanism through genome-wide approaches: it represses YAP/TEAD- and ER-driven enhancers by recruiting NuRD/coREST and removing H3K27 acetylation, and is essential for tumor cell proliferation and survival.\",\n      \"evidence\": \"Genome-wide CRISPR and shRNA screens, ChIP-seq, ATAC-seq, Hi-C, mass spectrometry, knockdown phenotyping\",\n      \"pmids\": [\"30082728\", \"29895970\", \"30380416\", \"29471243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRPS1 is targeted specifically to YAP/ER enhancers not fully resolved\", \"Relative contributions of NuRD versus coREST unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated tumor-suppressor activity in mammary epithelium via interferon-signaling suppression and lactogenic differentiation, and a developmental role in zygotic genome activation through histone-mark regulation.\",\n      \"evidence\": \"Conditional mammary KO, organoid culture, RNA-seq; embryo siRNA microinjection with histone mark immunofluorescence\",\n      \"pmids\": [\"31879358\", \"30712485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct interferon-pathway target genes of TRPS1 not all defined\", \"ZGA role rests on single-lab embryo knockdown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed TRPS1 cooperates with the Gli3 activator to directly activate Wnt5a during chondrocyte differentiation, reinforcing its dual repressor/activator capacity in skeletal development.\",\n      \"evidence\": \"ChIP and reporter assays at the Wnt5a URS1, Trps1/Gli3 double-knockout mouse analysis\",\n      \"pmids\": [\"31550480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of cooperative activation with Gli3A not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a transcription-independent oncogenic mechanism: TRPS1 reads H3K9me3 at heterochromatic replication origins via its GATA and IKAROS domains and promotes APC/C chromatin loading, driving origin refiring and genome amplification, lost in TRPS-associated mutants.\",\n      \"evidence\": \"Epigenomic decomposition, ChIP-seq, replication origin and APC/C loading assays, domain mutagenesis, tumor xenografts\",\n      \"pmids\": [\"33691114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRPS1 mechanistically recruits APC/C to chromatin not detailed\", \"Relationship between this chromatin-reader role and its corepressor role unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended TRPS1 transcriptional control to Leydig cell proliferation via direct regulation of Srcin1 and the Src/Akt/Ccnd1 pathway.\",\n      \"evidence\": \"ChIP-seq, ChIP-qPCR, RNA-seq, siRNA knockdown with signaling readouts\",\n      \"pmids\": [\"34185441\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Srcin1 regulation is repressive or activating not clearly framed\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a recurrent cancer mutation (R544Q) that gains pro-metastatic function in colorectal cancer through a TRPS1-ZEB1 axis.\",\n      \"evidence\": \"Single-cell exome sequencing, in vitro and in vivo invasion/migration assays\",\n      \"pmids\": [\"39307879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which R544Q alters TRPS1 activity not defined\", \"Whether the mutation affects DNA binding or partner recruitment untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRPS1's molecular activity is switched between transcriptional repression, transcriptional activation, and its non-transcriptional replication-origin/APC/C function in a context-specific manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model explaining repressor versus activator behavior at different promoters\", \"Targeting determinants directing TRPS1 to specific enhancers/origins undefined\", \"How post-translational modifications (SUMOylation) and partners integrate to set activity mode unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 6, 9, 11, 22, 23, 32]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 6, 9, 11, 30]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [30]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [23, 24, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 6, 9, 23, 24]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [18, 23, 24, 30]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 6, 9, 12, 16]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [23, 30, 34]}\n    ],\n    \"complexes\": [\"NuRD complex\", \"coREST complex\"],\n    \"partners\": [\"HDAC1\", \"HDAC4\", \"LC8a/DYNLL1\", \"RNF4\", \"UBC9\", \"Gli3\", \"cathepsin D/CTSD\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}