{"gene":"TWIST1","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2011,"finding":"TWIST1 forms homo- or hetero-dimers to bind the Nde1 E-box element and activate or repress target genes; it recruits the nucleosome remodeling and deacetylase (NuRD) complex to directly repress E-cadherin expression during EMT.","method":"Biochemical characterization of bHLH domain, chromatin immunoprecipitation, functional reporter assays","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 — replicated across multiple labs with ChIP and functional assays, foundational review summarizing mechanistic findings","pmids":["21876555"],"is_preprint":false},{"year":2005,"finding":"Dimerization partner choice by TWIST1 is regulated by protein kinase A- and protein phosphatase 2A-mediated phosphorylation of conserved helix I residues; multiple Saethre-Chotzen syndrome mutations alter PKA-mediated phosphorylation of TWIST1, disrupting normal dimer partner selection between TWIST1 and HAND2.","method":"In vivo phosphorylation assays, genetic epistasis in mouse limb, dominant-negative expression, domain mutagenesis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (phosphorylation assays, mouse genetics, mutagenesis), independently consistent with disease mutations","pmids":["15735646"],"is_preprint":false},{"year":2008,"finding":"Phosphoregulation of specific bHLH domain residues in TWIST1 alters dimerization partner affinities and DNA binding affinity in a cis-element-dependent manner, controlling cell fate decisions.","method":"Phosphorylation assays, dimerization partner binding assays, DNA binding (EMSA), mutagenesis","journal":"Current medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical methods, single-lab review summarizing original mechanistic data","pmids":["18855684"],"is_preprint":false},{"year":2010,"finding":"TWIST1 binds to the VE-cadherin promoter and enhances its transcriptional activity, while suppressing E-cadherin expression, to promote vasculogenic mimicry in hepatocellular carcinoma.","method":"Chromatin immunoprecipitation, transactivation (luciferase) assay, shRNA knockdown, overexpression","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assays, single lab","pmids":["19957372"],"is_preprint":false},{"year":2013,"finding":"TWIST1 expression in mammary epithelial cells induces CCL2 expression (not VEGF or bFGF), which recruits macrophages that are required for the proangiogenic response; attenuation of TWIST1 in vivo blocked macrophage recruitment and angiogenesis.","method":"In vitro expression assays, in vivo macrophage depletion, exogenous CCL2 rescue experiments","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (in vitro, in vivo depletion, rescue), clear mechanistic pathway","pmids":["23329645"],"is_preprint":false},{"year":2014,"finding":"p62 (SQSTM1) binds directly to TWIST1 and inhibits its degradation via both autophagosomal and proteasomal pathways, thereby stabilizing TWIST1 protein to promote cell proliferation and migration.","method":"Co-immunoprecipitation, autophagy-deficient mouse models, in vivo tumor growth assays","journal":"Proceedings of the National Academy of Sciences of the USA","confidence":"High","confidence_rationale":"Tier 2 — direct protein interaction (Co-IP), in vivo rescue, multiple readouts","pmids":["24927592"],"is_preprint":false},{"year":2013,"finding":"TGF-β1 upregulates TWIST1 expression through a cascade involving STAT3 phosphorylation and HIF-1α stabilization; both STAT3 and HIF-1α directly bind the TWIST1 promoter, and STAT3 also enhances TWIST1 expression indirectly through HIF-1α stabilization.","method":"siRNA silencing, dominant-negative STAT3, chromatin immunoprecipitation, promoter-reporter assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assays for direct binding, multiple silencing approaches, single lab","pmids":["23623921"],"is_preprint":false},{"year":2013,"finding":"TWIST1 interacts with the pro-neural factor SOX10 via its Twist-box domain and binds the PHOX2B promoter to repress its transcriptional activity, thereby controlling neural crest cell fate between ectodermal and mesodermal lineages.","method":"Conditional mouse knockout, promoter-reporter (luciferase), protein interaction assays, domain mutagenesis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model combined with direct promoter binding and protein interaction assays","pmids":["23555309"],"is_preprint":false},{"year":2014,"finding":"TWIST1 directly binds the FOXA1 proximal promoter, recruits the NuRD transcriptional repressor complex to de-acetylate H3K9, and inhibits AP-1 recruitment to silence FOXA1 expression, enabling breast cancer invasion and metastasis.","method":"ChIP, reporter assays, Co-IP for complex components, reconstitution of FOXA1 rescue in xenograft","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (ChIP, reporter, NuRD complex pulldown, in vivo xenograft rescue)","pmids":["27524420"],"is_preprint":false},{"year":2014,"finding":"TWIST1 inhibits TRIM29 promoter activity through direct binding to a cluster of E-box elements within the TRIM29 promoter, creating a negative regulatory feedback loop.","method":"Promoter-reporter assay, TWIST1 binding to E-box elements","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter binding demonstrated, single lab","pmids":["24950909"],"is_preprint":false},{"year":2015,"finding":"TWIST1 binds directly to the C3 (complement component 3) promoter and enhances its expression; TWIST1 and C3 co-localize at invasive tumor edges and in the neural crest and limb buds of mouse embryos.","method":"Promoter-reporter assay, chromatin immunoprecipitation, immunohistochemistry/colocalization","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assay for direct binding, single lab","pmids":["26718342"],"is_preprint":false},{"year":2015,"finding":"TWIST1 conditional knockout in skin reduces keratinocyte stem cell populations (α6-integrin+/CD34+ and label-retaining cells) and blocks tumor initiation and maintenance in a gene-dosage-dependent and partially p53-dependent manner, independent of EMT.","method":"Conditional knockout at different carcinogenesis stages, flow cytometry, apoptosis assays, proliferation assays","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 — conditional ablation at multiple stages with defined phenotypic readouts, epistasis with p53","pmids":["25575080"],"is_preprint":false},{"year":2016,"finding":"TWIST1 modulates vascular permeability and angiogenesis by regulating Tie2 expression; knockdown of TWIST1 in endothelial cells decreases Tie2 expression and phosphorylation, increases RhoA activity, disrupts cell-cell junctions, and increases permeability.","method":"siRNA knockdown, conditional knockout (Tie2-specific Twist1fl/fl), endothelial permeability assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific conditional knockout with defined phenotype plus in vitro mechanistic readouts","pmids":["24023872"],"is_preprint":false},{"year":2016,"finding":"TWIST1 phosphorylation at serine 42 (Ser42) is required for its control of angiogenesis through the angiopoietin-Tie2 pathway; a Twist1S42A phosphorylation-dead mutant decreases Tie2 expression and attenuates angiogenesis and collagen deposition in bleomycin-induced pulmonary fibrosis.","method":"Phospho-mutant construct, conditional knockout (Twist1fl/fl/Tie2-cre), in vitro sprouting assay, in vivo fibrin gel angiogenesis","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 — phospho-mutant mutagenesis plus in vivo conditional KO with mechanistic pathway validation","pmids":["27281171"],"is_preprint":false},{"year":2016,"finding":"TWIST1 homodimers (promoted by TGFβ-induced upregulation of ID proteins that compete for E12/E47) mediate fibroblast activation and tissue fibrosis; TGFβ/SMAD3 pathway induces TWIST1 in fibroblasts, and fibroblast-specific Twist1 deletion protects mice from experimental skin fibrosis.","method":"Co-immunoprecipitation (TWIST1, E12, ID proteins), fibroblast-specific conditional KO, bleomycin and TGFβR-constitutive-active models","journal":"Annals of the rheumatic diseases","confidence":"High","confidence_rationale":"Tier 2 — Co-IP for dimer composition, in vivo conditional KO in two fibrosis models","pmids":["27113414"],"is_preprint":false},{"year":2016,"finding":"TWIST1 is induced at low shear stress regions of arteries via a GATA4-dependent transcriptional mechanism, and EC-specific TWIST1 deletion in mice reduces atherosclerosis by inhibiting inflammation and EC proliferation.","method":"EC-specific conditional Twist1 KO, carotid artery model, gene silencing, qPCR/en face staining","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — in vivo conditional KO with defined phenotype, in vitro mechanistic follow-up","pmids":["27245171"],"is_preprint":false},{"year":2017,"finding":"Aurora kinase A (AURKA) phosphorylates TWIST1 at three sites, inhibiting its ubiquitination, increasing its transcriptional activity, and favoring its homodimerization; in turn, TWIST1 prevents AURKA degradation, establishing a feedback loop. Phosphorylation-dead TWIST1 acts as a dominant-negative and fully reverses AURKA-induced EMT.","method":"In vitro kinase assay, ubiquitination assay, co-immunoprecipitation, phospho-dead/mimic mutants, in vivo tumor formation","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted kinase assay + mutagenesis + in vivo validation","pmids":["28167680"],"is_preprint":false},{"year":2018,"finding":"TWIST1 binds the CUL2 promoter to activate its transcription and selectively promotes expression of Cul2 circular RNA (circ-10720) over Cul2 mRNA; circ-10720 acts as a miRNA sponge to increase vimentin expression during EMT.","method":"ChIP, reporter assays, circ-10720 knockdown, patient-derived xenograft and transgenic mouse models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — ChIP for direct binding, in vivo xenograft and transgenic model validation","pmids":["29844124"],"is_preprint":false},{"year":2018,"finding":"Wild-type p53 forms a complex with TWIST1 and the E3 ubiquitin ligase Pirh2 to promote ubiquitination and proteasomal degradation of TWIST1, thereby inhibiting EMT; mutant p53 loses this ability.","method":"Co-immunoprecipitation, ubiquitination assays, proteasome inhibition, p53 mutant constructs","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination assays, single lab","pmids":["30131448"],"is_preprint":false},{"year":2018,"finding":"TWIST1 and its E2A heterodimeric partners mutually regulate each other's stability post-translationally; the TWIST1-E2A heterodimer is preferentially degraded by harmine compared to TWIST1-TWIST1 homodimer, and E2A proteins are required for TWIST1-mediated functions.","method":"Protein stability assays, dimer-specific degradation assays, drug treatment, transgenic and PDX mouse models","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic dimer-specific degradation assays with in vivo validation, single lab","pmids":["28851812"],"is_preprint":false},{"year":2018,"finding":"MYCN and c-MYC directly bind E-box and INR elements in the TWIST1 promoter and activate its transcription, establishing TWIST1 as a direct MYC transcriptional target in neuroblastoma.","method":"Gel shift assay (EMSA), luciferase reporter assay, in silico E-box analysis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — EMSA and reporter assay for direct binding, single lab","pmids":["25475555"],"is_preprint":false},{"year":2019,"finding":"TRIB3 binds the WR domain of TWIST1 and stabilizes it by inhibiting ubiquitination; disruption of the TRIB3-TWIST1 interaction by a peptide analogue promotes TWIST1 degradation and reverses ATRA resistance in APL.","method":"Co-immunoprecipitation, ubiquitination assay, peptide disruption of protein-protein interaction, in vivo APL models","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 — direct interaction mapped to WR domain, ubiquitination assay, in vivo rescue","pmids":["31235507"],"is_preprint":false},{"year":2020,"finding":"USP4 binds to, deubiquitinates, and stabilizes TWIST1 protein, promoting lung cancer stemness; silencing USP4 leads to TWIST1 degradation and loss of cancer stem cell properties, rescuable by TWIST1 re-expression.","method":"Co-immunoprecipitation, deubiquitination assay, knockdown/overexpression, stem cell assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical deubiquitination assay, single lab","pmids":["32549341"],"is_preprint":false},{"year":2020,"finding":"USP18 interacts with TWIST1, removes its ubiquitin chains, and stabilizes it to promote EMT and glioblastoma invasion; TWIST1 re-expression fully rescues USP18-depletion phenotypes.","method":"Co-immunoprecipitation, ubiquitination assay, shRNA knockdown, in vivo tumor model","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — direct deubiquitination assay and rescue experiments, single lab","pmids":["32368392"],"is_preprint":false},{"year":2020,"finding":"CBX7 binds the E-box sequence to block TWIST1 from binding its target DNA, rendering TWIST1 transcriptionally nonfunctional in secondary ovarian cancer cells; deletion of CBX7 reactivates TWIST1-induced transcription and mesenchymal transformation.","method":"Chromatin binding assay, E-box competition assay, CBX7 knockout, in vivo tumorigenicity","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — direct E-box competition demonstrated, in vivo rescue, single lab","pmids":["32205869"],"is_preprint":false},{"year":2020,"finding":"Mutant CFTR intrinsically triggers EMT through TWIST1; CFTR modulator drugs reverse the CF EMT phenotype by restoring functional CFTR and reducing TWIST1-mediated EMT.","method":"CFTR-mutant cell lines and native tissue, EMT marker expression, drug rescue with CFTR modulators","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic link established with rescue experiments, multiple cellular models","pmids":["33106471"],"is_preprint":false},{"year":2020,"finding":"G3BP2 promotes TWIST1 ubiquitination and proteasomal degradation; α-parvin binding to G3BP2 prevents this interaction, thereby stabilizing TWIST1 and promoting breast cancer metastasis.","method":"Co-immunoprecipitation, ubiquitination assay, mutagenesis of α-parvin G3BP2-binding site, in vivo tumor progression","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — direct binding mapped by mutagenesis, ubiquitination assay, in vivo validation","pmids":["30804457"],"is_preprint":false},{"year":2021,"finding":"TWIST1 and chromatin regulators CHD7, CHD8, and WHSC1 form a TWIST1-chromatin regulatory module (TWIST1-CRM) in neural crest cells; perturbation of any core member causes abnormal NCC differentiation and craniofacial defects. TWIST1-CRM represses neural stem cell programs at low activity and commits NCCs to ectomesenchyme at high activity.","method":"BioID proximity labeling, network propagation analysis, combinatorial knockdown in cell models and mouse embryos","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — unbiased proximity proteomics plus multiple loss-of-function models in vivo","pmids":["33554859"],"is_preprint":false},{"year":2022,"finding":"Twist1 in macrophages directly activates galectin-3 transcription and regulates M2 macrophage polarization; Twist1 also controls macrophage chemotaxis partly through the CCL2/CCR2 axis. Macrophage-specific Twist1 ablation reduces renal fibrosis.","method":"Conditional macrophage-specific Twist1 knockout, ChIP (galectin-3 promoter), cytokine secretion assays, UUO model","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 2 — direct promoter binding by ChIP, conditional KO with mechanistic readout, in vivo model","pmids":["35182235"],"is_preprint":false},{"year":2023,"finding":"TWIST1 acetylation at K73/76 determines its co-activator versus co-repressor function: non-acetylated TWIST1-K73/76 recruits NuRD complex to repress epithelial target genes, while diacetylated TWIST1-acK73/76 binds BRD8 (a TIP60-Com component) to recruit TIP60-Com and activate mesenchymal genes and MYC. Knockdown of BRD8 abolishes TWIST1/TIP60-Com interaction and reduces TWIST1-activated gene expression.","method":"Co-immunoprecipitation, ChIP-seq, acetylation-mimetic/dead mutants, BRD8 knockdown, RNA-seq","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 — acetylation-dependent complex switching demonstrated by Co-IP, ChIP-seq, mutagenesis, and functional RNA-seq","pmids":["37680145"],"is_preprint":false},{"year":2023,"finding":"CDK1 phosphorylates USP29, which activates USP29's deubiquitinase activity toward TWIST1, thereby stabilizing TWIST1 and promoting EMT, chemoresistance, and metastasis in TNBC; CDK1 inhibition destabilizes TWIST1.","method":"In vitro kinase assay, ubiquitination assay, Co-immunoprecipitation, CDK1 genetic ablation, pharmacological inhibition","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted kinase assay plus deubiquitination assay, genetic and pharmacological inhibition in vivo","pmids":["36782089"],"is_preprint":false},{"year":2023,"finding":"USP13 directly interacts with TWIST1, cleaves K48-linked polyubiquitin chains added by FBXL14, and stabilizes TWIST1 protein; TWIST1 in turn transcriptionally represses USP13, forming a negative feedback loop.","method":"Co-immunoprecipitation, GST-pulldown, ubiquitination assay, ChIP and luciferase reporter","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 — direct interaction by GST-pulldown and Co-IP, ubiquitin linkage specificity assay, transcriptional feedback by ChIP","pmids":["36732432"],"is_preprint":false},{"year":2023,"finding":"FBXO3 stabilizes USP4 by disrupting the interaction between USP4 and DNPEP (aspartyl aminopeptidase), preventing DNPEP-mediated USP4 degradation; stabilized USP4 in turn deubiquitinates and stabilizes TWIST1 to promote breast cancer metastasis. PI3K-p110αH1047R facilitates FBXO3 phosphorylation and stabilization via ERK1.","method":"Co-immunoprecipitation, ubiquitination assay, FBXO3 mutagenesis (E3-dead), in vivo mouse metastasis assay","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 — domain mutagenesis of E3-ligase-dead construct, direct interaction mapping, in vivo validation","pmids":["38134227"],"is_preprint":false},{"year":2011,"finding":"TWIST1 directly binds to Bmi1 promoter E-box sequences and activates Bmi1 expression, linking EMT induction to cancer stemness via chromatin remodeling.","method":"Chromatin immunoprecipitation, reporter assays, head and neck cancer patient samples","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assays, patient sample correlation, single lab","pmids":["21919891"],"is_preprint":false},{"year":2011,"finding":"TWIST1 directly binds E-box sequences in the promoters of Tbx20, Cdh11, Sema3C, Rab39b, and Gadd45a in developing heart valve endocardial cushion cells, regulating proliferation and migration of valve mesenchymal cells.","method":"ChIP assay, candidate gene and global gene profiling, evolutionarily conserved E-box analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo ChIP confirming direct binding to multiple target promoters in tissue","pmids":["22242143"],"is_preprint":false},{"year":2015,"finding":"TWIST1 directly binds the promoters of Cyclin E1, E2F1, and c-Myc at canonical E-box motifs to regulate cell cycle progression at G1/S, promoting keratinocyte proliferation and skin tumor initiation.","method":"ChIP, conditional Twist1 KO in keratinocytes, cell cycle analysis, Western blot","journal":"Molecular carcinogenesis","confidence":"High","confidence_rationale":"Tier 2 — ChIP evidence for direct binding plus loss-of-function with defined cell cycle phenotype","pmids":["26013710"],"is_preprint":false},{"year":2016,"finding":"TWIST1 directly binds the promoters of Ddr2, Pcolce, and Tgfbi in cranial mesoderm, and these targets regulate extracellular matrix/cell-matrix interactions required for mesenchymal maintenance. ChIP-seq in an in vitro TWIST1-dependent mesenchymal model identified genome-wide TWIST1 binding sites.","method":"ChIP-seq, ChIP-PCR on embryonic tissues, luciferase reporter assays, Twist1 conditional KO","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP-seq plus validation by ChIP-PCR in vivo and reporter assay, conditional KO phenotype","pmids":["27546376"],"is_preprint":false},{"year":2013,"finding":"TWIST1 directly binds the FoxM1 promoter at an E-box motif and recruits p300 to induce FoxM1 mRNA transcription, thereby promoting gastric cancer cell proliferation.","method":"ChIP, reporter assay, knockdown/overexpression of Twist1 and FoxM1","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assay for direct binding and p300 co-recruitment, single lab","pmids":["24204899"],"is_preprint":false},{"year":2020,"finding":"TWIST1 drives smooth muscle cell proliferation in pulmonary hypertension by promoting proteasomal degradation of GATA-6; loss of GATA-6 reduces BMPR2 expression because GATA-6 directly binds the BMPR2 promoter. SMC-specific Twist1 deletion attenuates PH and vascular remodeling.","method":"SMC-specific Twist1 conditional KO, mass spectrometry, Co-IP, ChIP, in vitro SMC proliferation","journal":"American journal of respiratory and critical care medicine","confidence":"High","confidence_rationale":"Tier 2 — conditional KO in two animal models, ChIP for GATA-6/BMPR2, Co-IP, MS identification of interactors","pmids":["32692930"],"is_preprint":false},{"year":2019,"finding":"TWIST1 directly induces expression of discoidin domain receptor 2 (DDR2) in ovarian cancer cells, and DDR2 stabilizes SNAIL1 to sustain the mesenchymal phenotype and enable peritoneal metastasis.","method":"shRNA knockdown, overexpression, in vivo metastasis model, patient-derived tumor cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined metastatic phenotype, patient correlation, single lab","pmids":["29348456"],"is_preprint":false},{"year":2015,"finding":"TWIST1 directly binds to the miR-584 genomic locus to activate its transcription (confirmed by ChIP), and miR-584 targets TUSC2 to promote resistance to apoptosis in thyroid cancer cells.","method":"ChIP, miRNome profiling, luciferase assay, overexpression/anti-miR experiments","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — direct TWIST1 binding to miR-584 by ChIP, functional rescue experiments, single lab","pmids":["27661106"],"is_preprint":false},{"year":2008,"finding":"TWIST1 expression in Th1 effector memory cells is induced by NF-κB, NFAT, and IL-12/STAT4 signaling, and TWIST1 in turn limits expression of IFN-γ, IL-2, and TNF-α to autoregulate Th1-mediated immunopathology.","method":"T cell stimulation assays, transcription factor inhibition (dominant negatives and pharmacological), adoptive transfer models of delayed-type hypersensitivity and antigen-induced arthritis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple transcription factor pathway inhibition, in vivo mouse models with defined phenotype","pmids":["18663125"],"is_preprint":false},{"year":2014,"finding":"TWIST1 dissemination from primary mammary epithelium requires E-cadherin; Twist1 expression induces changes in extracellular matrix and cell-matrix adhesion genes (not cell-cell adhesion genes), and E-cadherin knockdown strongly inhibits Twist1-induced single-cell dissemination.","method":"3D mammary organoid culture, live imaging, RNA-seq transcriptional profiling, E-cadherin knockdown, conditional mouse model","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, unexpected mechanistic finding (E-cadherin required for dissemination), well-controlled genetic models","pmids":["24590176"],"is_preprint":false},{"year":2004,"finding":"TWIST1 (H-Twist) overexpression inhibits the ARF/p53 apoptotic pathway in N-Myc-amplified neuroblastoma, enabling oncogenic cooperation between TWIST1 and N-Myc to cause cell transformation and circumvent p53-dependent apoptosis.","method":"Pangenomic cDNA microarray, functional cell transformation assays, apoptosis assays","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 — microarray identification combined with functional transformation assays, single lab","pmids":["15607966"],"is_preprint":false},{"year":2018,"finding":"Enhancers eTw-5, eTw-6, and eTw-7 within the TWIST1-HDAC9 locus physically interact with the Twist1 promoter (by 4C-seq) in limb bud and branchial arch; LMX1B and TFAP2 bind these enhancers to modulate TWIST1 transcription. CRISPR deletion of eTw5-7 reduces Twist1 expression and causes pre-axial polydactyly.","method":"4C-seq, ChIP-seq (p300, H3K27ac), CRISPR/Cas9 enhancer deletion, zebrafish/mouse enhancer assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1-2 — 4C-seq for physical interaction, CRISPR deletion producing phenotype, transcription factor binding identified","pmids":["30372441"],"is_preprint":false},{"year":2023,"finding":"TWIST1 is highly expressed in IPF myofibroblasts with selectively increased chromatin accessibility at the TWIST1 locus; Twist1 overexpression in COL1A2-expressing fibroblasts increases collagen synthesis and upregulates fibrosis-related gene programs.","method":"Single-nucleus ATAC-seq, scRNA-seq integration, Twist1 overexpression in bleomycin-injured Cre-ER mice, RNA-seq","journal":"European respiratory journal","confidence":"High","confidence_rationale":"Tier 1-2 — single-nucleus chromatin accessibility plus in vivo overexpression mouse model with transcriptomic readout","pmids":["37142338"],"is_preprint":false}],"current_model":"TWIST1 is a bHLH transcription factor that forms homo- and hetero-dimers regulated by phosphorylation (via PKA, AURKA, CDK1) and acetylation (at K73/76), determining whether it recruits the NuRD co-repressor complex to silence epithelial genes or the TIP60-Com co-activator complex to activate mesenchymal and proliferative genes; its protein stability is controlled by multiple deubiquitinases (USP4, USP13, USP18, USP29) and E3 ligase complexes (FBXL14, Pirh2), and its activity promotes EMT, cancer metastasis, vascular remodeling, fibrosis, and immune regulation through direct transcriptional control of E-cadherin, VE-cadherin, Bmi1, FoxM1, CCL2, Tie2, GATA-6/BMPR2, and many other targets."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing that TWIST1 has oncogenic activity beyond EMT: TWIST1 was shown to cooperate with N-Myc by suppressing the ARF/p53 apoptotic pathway, revealing a pro-survival transcriptional function.","evidence":"cDNA microarray and functional transformation/apoptosis assays in neuroblastoma cells","pmids":["15607966"],"confidence":"Medium","gaps":["Mechanism of ARF pathway suppression not molecularly defined","No direct promoter binding to ARF pathway genes shown"]},{"year":2005,"claim":"Resolving how TWIST1 dimer partner choice is determined: PKA-mediated phosphorylation of helix I residues was shown to regulate whether TWIST1 homodimerizes or heterodimerizes with HAND2, and Saethre-Chotzen syndrome mutations disrupt this phosphoregulation.","evidence":"In vivo phosphorylation assays, mouse limb genetics, domain mutagenesis","pmids":["15735646"],"confidence":"High","gaps":["Crystal structure of phosphorylated versus unphosphorylated dimers not resolved","Full spectrum of phosphosites controlling partner choice not mapped"]},{"year":2008,"claim":"Extending TWIST1 function to immune regulation: TWIST1 was found to be induced in Th1 effector memory cells via NF-κB/NFAT/STAT4 and to limit IFN-γ, IL-2, and TNF-α expression, establishing a negative feedback loop restraining immunopathology.","evidence":"T cell stimulation, transcription factor inhibition, adoptive transfer arthritis models","pmids":["18663125"],"confidence":"High","gaps":["Direct promoter binding to cytokine loci not demonstrated by ChIP","Mechanism of transcriptional repression in T cells unclear"]},{"year":2011,"claim":"Identifying the NuRD complex as TWIST1's repressive effector: TWIST1 was shown to recruit NuRD to the E-cadherin promoter to repress transcription, and to directly activate Bmi1 via E-box binding, linking EMT to stemness.","evidence":"ChIP, reporter assays, biochemical characterization of bHLH domain","pmids":["21876555","21919891"],"confidence":"High","gaps":["Which NuRD subunits directly contact TWIST1 not identified","Whether NuRD recruitment requires specific post-translational modification state was unknown"]},{"year":2013,"claim":"Revealing TWIST1's paracrine and developmental regulatory roles: TWIST1 was shown to induce CCL2 to recruit pro-angiogenic macrophages, to interact with SOX10 via its Twist-box to repress PHOX2B and control neural crest fate, and to recruit p300 to the FoxM1 promoter for proliferative gene activation.","evidence":"In vivo macrophage depletion/rescue, conditional mouse KO with promoter-reporter assays, ChIP","pmids":["23329645","23555309","24204899"],"confidence":"High","gaps":["Whether CCL2 induction is direct or indirect not fully resolved","Structural basis of SOX10-Twist-box interaction not determined"]},{"year":2014,"claim":"Establishing TWIST1 protein stability as a regulatory node: p62/SQSTM1 was shown to stabilize TWIST1 by blocking both proteasomal and autophagosomal degradation, while wild-type p53 recruited Pirh2 to ubiquitinate TWIST1, and E-cadherin was paradoxically shown to be required for TWIST1-induced cell dissemination.","evidence":"Co-IP, autophagy-deficient models, ubiquitination assays, 3D organoid live imaging","pmids":["24927592","30131448","24590176"],"confidence":"High","gaps":["Which ubiquitin linkage types are added by Pirh2 not defined","How E-cadherin mechanistically promotes dissemination despite being a TWIST1-repressed target remains unresolved"]},{"year":2015,"claim":"Demonstrating TWIST1's EMT-independent roles in stem cell maintenance and cell cycle: conditional Twist1 KO in skin depleted keratinocyte stem cells and blocked tumor initiation in a p53-dependent manner, while ChIP confirmed direct binding to Cyclin E1, E2F1, and c-Myc promoters.","evidence":"Conditional KO at multiple carcinogenesis stages, flow cytometry, ChIP, cell cycle analysis","pmids":["25575080","26013710"],"confidence":"High","gaps":["Whether stem cell depletion is cell-autonomous or requires niche signals not fully resolved","Relative contribution of each cell cycle target not dissected"]},{"year":2016,"claim":"Defining TWIST1's vascular and fibrotic functions: Ser42 phosphorylation was required for Tie2 regulation and angiogenesis, TGFβ-induced ID proteins shifted TWIST1 toward homodimers to drive fibroblast activation and fibrosis, and EC-specific TWIST1 deletion reduced atherosclerosis.","evidence":"Phospho-mutant constructs, endothelial and fibroblast conditional KOs, bleomycin fibrosis models, ChIP-seq","pmids":["27281171","27113414","27245171","27546376"],"confidence":"High","gaps":["Kinase responsible for Ser42 phosphorylation not identified","Whether homodimer-specific target gene sets differ in fibroblasts versus endothelial cells not determined"]},{"year":2017,"claim":"Revealing a TWIST1-AURKA mutual stabilization loop: Aurora kinase A phosphorylation of TWIST1 at three sites inhibited ubiquitination and favored homodimerization, while TWIST1 reciprocally prevented AURKA degradation.","evidence":"In vitro kinase assay, ubiquitination assay, phospho-dead/mimic mutants, in vivo tumor formation","pmids":["28167680"],"confidence":"High","gaps":["Whether AURKA phosphorylation sites overlap with PKA sites not clarified","Structural mechanism of phosphorylation-dependent ubiquitination resistance unknown"]},{"year":2018,"claim":"Expanding the regulatory landscape of TWIST1: upstream enhancers eTw-5/6/7 were shown to physically contact the TWIST1 promoter and be bound by LMX1B/TFAP2, TWIST1 activated CUL2/circ-10720 for EMT, and E2A heterodimer stability was shown to differ from homodimer stability.","evidence":"4C-seq, CRISPR enhancer deletion causing polydactyly, ChIP, dimer-specific degradation assays","pmids":["30372441","29844124","28851812"],"confidence":"High","gaps":["Complete enhancer logic for tissue-specific TWIST1 expression not mapped","Functional significance of circular RNA versus mRNA output ratio unknown"]},{"year":2020,"claim":"Identifying multiple deubiquitinases and adaptor proteins controlling TWIST1 turnover: USP4, USP18, and the G3BP2/α-parvin axis were each shown to regulate TWIST1 ubiquitination status, and TWIST1 was shown to promote pulmonary hypertension by degrading GATA-6.","evidence":"Co-IP and deubiquitination assays, conditional SMC-specific Twist1 KO, ubiquitination assays with domain mapping","pmids":["32549341","32368392","30804457","32692930"],"confidence":"High","gaps":["Relative contributions of individual DUBs in a single tissue context not compared","Whether USP4 and USP18 act on the same or different ubiquitin chain types on TWIST1 not resolved"]},{"year":2021,"claim":"Identifying a TWIST1-chromatin regulatory module (CRM) in neural crest: BioID proximity labeling revealed CHD7, CHD8, and WHSC1 as core TWIST1 partners that collectively control NCC differentiation and craniofacial morphogenesis.","evidence":"BioID proximity proteomics, combinatorial knockdown in cells and mouse embryos","pmids":["33554859"],"confidence":"High","gaps":["Whether TWIST1-CRM uses the same acetylation switch as NuRD/TIP60-Com not tested","Direct versus indirect interactions within the CRM not fully resolved"]},{"year":2023,"claim":"Resolving the acetylation switch governing TWIST1 co-factor choice: K73/K76 diacetylation was shown to switch TWIST1 from NuRD-mediated repression to BRD8/TIP60-Com-mediated activation, and CDK1-phosphorylated USP29 was identified as another stabilizing DUB, while FBXL14 was identified as the E3 ligase counteracted by USP13.","evidence":"Acetylation-mimetic/dead mutants with ChIP-seq and RNA-seq, in vitro kinase and deubiquitination assays, GST-pulldown","pmids":["37680145","36782089","36732432"],"confidence":"High","gaps":["Acetyltransferase responsible for K73/K76 acetylation not identified","How the acetylation switch integrates with phosphorylation-dependent dimer choice is unknown","Whether the NuRD-to-TIP60 switch operates in non-cancer developmental contexts not tested"]},{"year":null,"claim":"The acetyltransferase writing K73/K76, the structural basis for acetylation-dependent cofactor switching, the integration of phosphorylation and acetylation codes on a single TWIST1 molecule, and the tissue-specific hierarchy among multiple DUBs remain undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["Identity of K73/K76 acetyltransferase unknown","No structural model of TWIST1 bound to NuRD versus TIP60-Com","Relative hierarchy of USP4/USP13/USP18/USP29 in physiological tissues not established","How enhancer-level and post-translational regulation are coordinated across tissues remains open"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,8,29,33,35,37]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,8,9,10,33,34,35,36]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,8,29,36]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,8,29,33,35,36,37]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[27,29]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,7,27,34,44]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,13,14,38]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[41,28]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,16,18,22,23,30,31]}],"complexes":["NuRD complex","TIP60-Com (NuA4)","TWIST1-CRM (CHD7/CHD8/WHSC1)"],"partners":["E2A","HAND2","SOX10","BRD8","AURKA","USP4","USP29","TRIB3"],"other_free_text":[]},"mechanistic_narrative":"TWIST1 is a basic helix-loop-helix (bHLH) transcription factor that functions as a master regulator of epithelial-mesenchymal transition (EMT), mesenchymal cell fate, and tissue remodeling by forming context-dependent homo- or heterodimers whose partner choice and transcriptional output are controlled by phosphorylation and acetylation. Non-acetylated TWIST1 recruits the NuRD co-repressor complex to silence epithelial genes such as E-cadherin and FOXA1, whereas diacetylation at K73/K76 switches its interaction to the TIP60-Com co-activator complex via BRD8, enabling activation of mesenchymal and proliferative targets including MYC, Bmi1, FoxM1, and Tie2 [PMID:37680145, PMID:21876555, PMID:27524420, PMID:24204899]. Protein stability is tightly regulated by multiple deubiquitinases (USP4, USP13, USP18, USP29) and E3 ligase pathways (FBXL14, Pirh2, G3BP2), with upstream kinases including PKA, Aurora A, and CDK1 controlling dimer composition, ubiquitin susceptibility, and transcriptional potency [PMID:15735646, PMID:28167680, PMID:36782089, PMID:36732432, PMID:30131448]. Beyond its canonical role in cancer metastasis and stemness, TWIST1 directs neural crest cell differentiation through a chromatin regulatory module containing CHD7/CHD8/WHSC1, regulates vascular integrity and angiogenesis through the angiopoietin-Tie2 axis, drives tissue fibrosis in lung and skin, and limits Th1 cytokine production to restrain immunopathology [PMID:33554859, PMID:27281171, PMID:37142338, PMID:18663125]."},"prefetch_data":{"uniprot":{"accession":"Q15672","full_name":"Twist-related protein 1","aliases":["Class A basic helix-loop-helix protein 38","bHLHa38","H-twist"],"length_aa":202,"mass_kda":21.0,"function":"Acts as a transcriptional regulator. Inhibits myogenesis by sequestrating E proteins, inhibiting trans-activation by MEF2, and inhibiting DNA-binding by MYOD1 through physical interaction. This interaction probably involves the basic domains of both proteins. Also represses expression of pro-inflammatory cytokines such as TNFA and IL1B. Regulates cranial suture patterning and fusion. Activates transcription as a heterodimer with E proteins. Regulates gene expression differentially, depending on dimer composition. Homodimers induce expression of FGFR2 and POSTN while heterodimers repress FGFR2 and POSTN expression and induce THBS1 expression. Heterodimerization is also required for osteoblast differentiation. Represses the activity of the circadian transcriptional activator: NPAS2-BMAL1 heterodimer (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q15672/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TWIST1","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TWIST1","total_profiled":1310},"omim":[{"mim_id":"621080","title":"HETEROTAXY, VISCERAL, 14, AUTOSOMAL; HTX14","url":"https://www.omim.org/entry/621080"},{"mim_id":"620457","title":"AURICULOCONDYLAR SYNDROME 4; ARCND4","url":"https://www.omim.org/entry/620457"},{"mim_id":"620408","title":"MICRO RNA 337; MIR337","url":"https://www.omim.org/entry/620408"},{"mim_id":"619700","title":"CILIATED LEFT-RIGHT ORGANIZER PROTEIN CONTAINING ZP-N DOMAINS; CIROZ","url":"https://www.omim.org/entry/619700"},{"mim_id":"618736","title":"STRUCTURAL BRAIN ANOMALIES WITH IMPAIRED INTELLECTUAL DEVELOPMENT AND CRANIOSYNOSTOSIS; BAIDCS","url":"https://www.omim.org/entry/618736"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"breast","ntpm":25.3}],"url":"https://www.proteinatlas.org/search/TWIST1"},"hgnc":{"alias_symbol":["SCS","H-twist","BPES2","bHLHa38","CRS1"],"prev_symbol":["ACS3","BPES3","TWIST","CRS"]},"alphafold":{"accession":"Q15672","domains":[{"cath_id":"-","chopping":"137-202","consensus_level":"medium","plddt":72.9024,"start":137,"end":202},{"cath_id":"1.20.5","chopping":"102-135","consensus_level":"medium","plddt":94.0412,"start":102,"end":135}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15672","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15672-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15672-F1-predicted_aligned_error_v6.png","plddt_mean":66.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TWIST1","jax_strain_url":"https://www.jax.org/strain/search?query=TWIST1"},"sequence":{"accession":"Q15672","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15672.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15672/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15672"}},"corpus_meta":[{"pmid":"21876555","id":"PMC_21876555","title":"Normal 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tumor tissues and voided urine in urinary bladder cancer patients.","date":"2013","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23682613","citation_count":37,"is_preprint":false},{"pmid":"32368392","id":"PMC_32368392","title":"USP18 deubiquitinates and stabilizes Twist1 to promote epithelial-mesenchymal transition in glioblastoma cells.","date":"2020","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32368392","citation_count":35,"is_preprint":false},{"pmid":"39024569","id":"PMC_39024569","title":"TWIST1+FAP+ fibroblasts in the pathogenesis of intestinal fibrosis in Crohn's disease.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/39024569","citation_count":34,"is_preprint":false},{"pmid":"27724883","id":"PMC_27724883","title":"DNMT3A mutation leads to leukemic extramedullary infiltration mediated by TWIST1.","date":"2016","source":"Journal of hematology & 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metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24848707","citation_count":27,"is_preprint":false},{"pmid":"37142338","id":"PMC_37142338","title":"Single-nucleus chromatin accessibility identifies a critical role for TWIST1 in idiopathic pulmonary fibrosis myofibroblast activity.","date":"2023","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/37142338","citation_count":25,"is_preprint":false},{"pmid":"25561797","id":"PMC_25561797","title":"Twist1 correlates with poor differentiation and progression in gastric adenocarcinoma via elevation of FGFR2 expression.","date":"2014","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/25561797","citation_count":24,"is_preprint":false},{"pmid":"26013710","id":"PMC_26013710","title":"Twist1 regulates keratinocyte proliferation and skin tumor promotion.","date":"2015","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/26013710","citation_count":23,"is_preprint":false},{"pmid":"34369383","id":"PMC_34369383","title":"Twist1 in podocytes ameliorates podocyte injury and proteinuria by limiting CCL2-dependent macrophage infiltration.","date":"2021","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/34369383","citation_count":23,"is_preprint":false},{"pmid":"32461589","id":"PMC_32461589","title":"Sox13 promotes hepatocellular carcinoma metastasis by transcriptionally activating Twist1.","date":"2020","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32461589","citation_count":23,"is_preprint":false},{"pmid":"30509092","id":"PMC_30509092","title":"KLF11 promotes gastric cancer invasion and migration by increasing Twist1 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chemosensitivity of FaDu cells.","date":"2014","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/24805866","citation_count":21,"is_preprint":false},{"pmid":"28177885","id":"PMC_28177885","title":"Aminopeptidase A initiates tumorigenesis and enhances tumor cell stemness via TWIST1 upregulation in colorectal cancer.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28177885","citation_count":21,"is_preprint":false},{"pmid":"31669261","id":"PMC_31669261","title":"TWIST1 Alleviates Hypoxia-induced Damage of Trophoblast Cells by inhibiting mitochondrial apoptosis pathway.","date":"2019","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/31669261","citation_count":21,"is_preprint":false},{"pmid":"26487719","id":"PMC_26487719","title":"Twist1 Is Essential for Tooth Morphogenesis and Odontoblast Differentiation.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26487719","citation_count":21,"is_preprint":false},{"pmid":"29405733","id":"PMC_29405733","title":"miR-16-1-3p targets TWIST1 to inhibit cell proliferation and invasion in NSCLC.","date":"2018","source":"Bratislavske lekarske listy","url":"https://pubmed.ncbi.nlm.nih.gov/29405733","citation_count":20,"is_preprint":false},{"pmid":"34660572","id":"PMC_34660572","title":"Obesity Inhibits Angiogenesis Through TWIST1-SLIT2 Signaling.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34660572","citation_count":19,"is_preprint":false},{"pmid":"38134227","id":"PMC_38134227","title":"FBXO3 stabilizes USP4 and Twist1 to promote PI3K-mediated breast cancer metastasis.","date":"2023","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/38134227","citation_count":19,"is_preprint":false},{"pmid":"33006113","id":"PMC_33006113","title":"TWIST1 upregulation affects E-cadherin expression in brain metastases.","date":"2020","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/33006113","citation_count":19,"is_preprint":false},{"pmid":"35242497","id":"PMC_35242497","title":"TWIST1-EP300 Expedites Gastric Cancer Cell Resistance to Apatinib by Activating the Expression of COL1A2.","date":"2022","source":"Analytical cellular pathology (Amsterdam)","url":"https://pubmed.ncbi.nlm.nih.gov/35242497","citation_count":19,"is_preprint":false},{"pmid":"36732432","id":"PMC_36732432","title":"USP13 promotes breast cancer metastasis through FBXL14-induced Twist1 ubiquitination.","date":"2023","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/36732432","citation_count":19,"is_preprint":false},{"pmid":"25597482","id":"PMC_25597482","title":"Over-expression of miR-10b in NPC patients: correlation with LMP1 and Twist1.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25597482","citation_count":19,"is_preprint":false},{"pmid":"29891550","id":"PMC_29891550","title":"The role of Twist1 in mutant huntingtin-induced transcriptional alterations and neurotoxicity.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29891550","citation_count":19,"is_preprint":false},{"pmid":"36463941","id":"PMC_36463941","title":"The potential of sertoli cells (SCs) derived exosomes and its therapeutic efficacy in male reproductive disorders.","date":"2022","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36463941","citation_count":19,"is_preprint":false},{"pmid":"30556860","id":"PMC_30556860","title":"Twist1/2 activates MMP2 expression via binding to its promoter in colorectal 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cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28873262","citation_count":18,"is_preprint":false},{"pmid":"30040876","id":"PMC_30040876","title":"Disruption of TWIST1 translation by 5' UTR variants in Saethre-Chotzen syndrome.","date":"2018","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/30040876","citation_count":18,"is_preprint":false},{"pmid":"21883379","id":"PMC_21883379","title":"Linkage between Twist1 and Bmi1: molecular mechanism of cancer metastasis/stemness and clinical implications.","date":"2012","source":"Clinical and experimental pharmacology & physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21883379","citation_count":17,"is_preprint":false},{"pmid":"30591455","id":"PMC_30591455","title":"Twist1 Correlates With Epithelial-Mesenchymal Transition Markers Fibronectin and Vimentin in Adrenocortical Tumors.","date":"2019","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30591455","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49426,"output_tokens":9549,"usd":0.145757},"stage2":{"model":"claude-opus-4-6","input_tokens":13556,"output_tokens":3855,"usd":0.246232},"total_usd":0.391989,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"TWIST1 forms homo- or hetero-dimers to bind the Nde1 E-box element and activate or repress target genes; it recruits the nucleosome remodeling and deacetylase (NuRD) complex to directly repress E-cadherin expression during EMT.\",\n      \"method\": \"Biochemical characterization of bHLH domain, chromatin immunoprecipitation, functional reporter assays\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across multiple labs with ChIP and functional assays, foundational review summarizing mechanistic findings\",\n      \"pmids\": [\"21876555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Dimerization partner choice by TWIST1 is regulated by protein kinase A- and protein phosphatase 2A-mediated phosphorylation of conserved helix I residues; multiple Saethre-Chotzen syndrome mutations alter PKA-mediated phosphorylation of TWIST1, disrupting normal dimer partner selection between TWIST1 and HAND2.\",\n      \"method\": \"In vivo phosphorylation assays, genetic epistasis in mouse limb, dominant-negative expression, domain mutagenesis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (phosphorylation assays, mouse genetics, mutagenesis), independently consistent with disease mutations\",\n      \"pmids\": [\"15735646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Phosphoregulation of specific bHLH domain residues in TWIST1 alters dimerization partner affinities and DNA binding affinity in a cis-element-dependent manner, controlling cell fate decisions.\",\n      \"method\": \"Phosphorylation assays, dimerization partner binding assays, DNA binding (EMSA), mutagenesis\",\n      \"journal\": \"Current medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods, single-lab review summarizing original mechanistic data\",\n      \"pmids\": [\"18855684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TWIST1 binds to the VE-cadherin promoter and enhances its transcriptional activity, while suppressing E-cadherin expression, to promote vasculogenic mimicry in hepatocellular carcinoma.\",\n      \"method\": \"Chromatin immunoprecipitation, transactivation (luciferase) assay, shRNA knockdown, overexpression\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assays, single lab\",\n      \"pmids\": [\"19957372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TWIST1 expression in mammary epithelial cells induces CCL2 expression (not VEGF or bFGF), which recruits macrophages that are required for the proangiogenic response; attenuation of TWIST1 in vivo blocked macrophage recruitment and angiogenesis.\",\n      \"method\": \"In vitro expression assays, in vivo macrophage depletion, exogenous CCL2 rescue experiments\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (in vitro, in vivo depletion, rescue), clear mechanistic pathway\",\n      \"pmids\": [\"23329645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"p62 (SQSTM1) binds directly to TWIST1 and inhibits its degradation via both autophagosomal and proteasomal pathways, thereby stabilizing TWIST1 protein to promote cell proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation, autophagy-deficient mouse models, in vivo tumor growth assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the USA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein interaction (Co-IP), in vivo rescue, multiple readouts\",\n      \"pmids\": [\"24927592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TGF-β1 upregulates TWIST1 expression through a cascade involving STAT3 phosphorylation and HIF-1α stabilization; both STAT3 and HIF-1α directly bind the TWIST1 promoter, and STAT3 also enhances TWIST1 expression indirectly through HIF-1α stabilization.\",\n      \"method\": \"siRNA silencing, dominant-negative STAT3, chromatin immunoprecipitation, promoter-reporter assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assays for direct binding, multiple silencing approaches, single lab\",\n      \"pmids\": [\"23623921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TWIST1 interacts with the pro-neural factor SOX10 via its Twist-box domain and binds the PHOX2B promoter to repress its transcriptional activity, thereby controlling neural crest cell fate between ectodermal and mesodermal lineages.\",\n      \"method\": \"Conditional mouse knockout, promoter-reporter (luciferase), protein interaction assays, domain mutagenesis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model combined with direct promoter binding and protein interaction assays\",\n      \"pmids\": [\"23555309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TWIST1 directly binds the FOXA1 proximal promoter, recruits the NuRD transcriptional repressor complex to de-acetylate H3K9, and inhibits AP-1 recruitment to silence FOXA1 expression, enabling breast cancer invasion and metastasis.\",\n      \"method\": \"ChIP, reporter assays, Co-IP for complex components, reconstitution of FOXA1 rescue in xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (ChIP, reporter, NuRD complex pulldown, in vivo xenograft rescue)\",\n      \"pmids\": [\"27524420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TWIST1 inhibits TRIM29 promoter activity through direct binding to a cluster of E-box elements within the TRIM29 promoter, creating a negative regulatory feedback loop.\",\n      \"method\": \"Promoter-reporter assay, TWIST1 binding to E-box elements\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding demonstrated, single lab\",\n      \"pmids\": [\"24950909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TWIST1 binds directly to the C3 (complement component 3) promoter and enhances its expression; TWIST1 and C3 co-localize at invasive tumor edges and in the neural crest and limb buds of mouse embryos.\",\n      \"method\": \"Promoter-reporter assay, chromatin immunoprecipitation, immunohistochemistry/colocalization\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay for direct binding, single lab\",\n      \"pmids\": [\"26718342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TWIST1 conditional knockout in skin reduces keratinocyte stem cell populations (α6-integrin+/CD34+ and label-retaining cells) and blocks tumor initiation and maintenance in a gene-dosage-dependent and partially p53-dependent manner, independent of EMT.\",\n      \"method\": \"Conditional knockout at different carcinogenesis stages, flow cytometry, apoptosis assays, proliferation assays\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional ablation at multiple stages with defined phenotypic readouts, epistasis with p53\",\n      \"pmids\": [\"25575080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TWIST1 modulates vascular permeability and angiogenesis by regulating Tie2 expression; knockdown of TWIST1 in endothelial cells decreases Tie2 expression and phosphorylation, increases RhoA activity, disrupts cell-cell junctions, and increases permeability.\",\n      \"method\": \"siRNA knockdown, conditional knockout (Tie2-specific Twist1fl/fl), endothelial permeability assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific conditional knockout with defined phenotype plus in vitro mechanistic readouts\",\n      \"pmids\": [\"24023872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TWIST1 phosphorylation at serine 42 (Ser42) is required for its control of angiogenesis through the angiopoietin-Tie2 pathway; a Twist1S42A phosphorylation-dead mutant decreases Tie2 expression and attenuates angiogenesis and collagen deposition in bleomycin-induced pulmonary fibrosis.\",\n      \"method\": \"Phospho-mutant construct, conditional knockout (Twist1fl/fl/Tie2-cre), in vitro sprouting assay, in vivo fibrin gel angiogenesis\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — phospho-mutant mutagenesis plus in vivo conditional KO with mechanistic pathway validation\",\n      \"pmids\": [\"27281171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TWIST1 homodimers (promoted by TGFβ-induced upregulation of ID proteins that compete for E12/E47) mediate fibroblast activation and tissue fibrosis; TGFβ/SMAD3 pathway induces TWIST1 in fibroblasts, and fibroblast-specific Twist1 deletion protects mice from experimental skin fibrosis.\",\n      \"method\": \"Co-immunoprecipitation (TWIST1, E12, ID proteins), fibroblast-specific conditional KO, bleomycin and TGFβR-constitutive-active models\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP for dimer composition, in vivo conditional KO in two fibrosis models\",\n      \"pmids\": [\"27113414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TWIST1 is induced at low shear stress regions of arteries via a GATA4-dependent transcriptional mechanism, and EC-specific TWIST1 deletion in mice reduces atherosclerosis by inhibiting inflammation and EC proliferation.\",\n      \"method\": \"EC-specific conditional Twist1 KO, carotid artery model, gene silencing, qPCR/en face staining\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo conditional KO with defined phenotype, in vitro mechanistic follow-up\",\n      \"pmids\": [\"27245171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Aurora kinase A (AURKA) phosphorylates TWIST1 at three sites, inhibiting its ubiquitination, increasing its transcriptional activity, and favoring its homodimerization; in turn, TWIST1 prevents AURKA degradation, establishing a feedback loop. Phosphorylation-dead TWIST1 acts as a dominant-negative and fully reverses AURKA-induced EMT.\",\n      \"method\": \"In vitro kinase assay, ubiquitination assay, co-immunoprecipitation, phospho-dead/mimic mutants, in vivo tumor formation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted kinase assay + mutagenesis + in vivo validation\",\n      \"pmids\": [\"28167680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TWIST1 binds the CUL2 promoter to activate its transcription and selectively promotes expression of Cul2 circular RNA (circ-10720) over Cul2 mRNA; circ-10720 acts as a miRNA sponge to increase vimentin expression during EMT.\",\n      \"method\": \"ChIP, reporter assays, circ-10720 knockdown, patient-derived xenograft and transgenic mouse models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP for direct binding, in vivo xenograft and transgenic model validation\",\n      \"pmids\": [\"29844124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wild-type p53 forms a complex with TWIST1 and the E3 ubiquitin ligase Pirh2 to promote ubiquitination and proteasomal degradation of TWIST1, thereby inhibiting EMT; mutant p53 loses this ability.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, proteasome inhibition, p53 mutant constructs\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assays, single lab\",\n      \"pmids\": [\"30131448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TWIST1 and its E2A heterodimeric partners mutually regulate each other's stability post-translationally; the TWIST1-E2A heterodimer is preferentially degraded by harmine compared to TWIST1-TWIST1 homodimer, and E2A proteins are required for TWIST1-mediated functions.\",\n      \"method\": \"Protein stability assays, dimer-specific degradation assays, drug treatment, transgenic and PDX mouse models\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dimer-specific degradation assays with in vivo validation, single lab\",\n      \"pmids\": [\"28851812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MYCN and c-MYC directly bind E-box and INR elements in the TWIST1 promoter and activate its transcription, establishing TWIST1 as a direct MYC transcriptional target in neuroblastoma.\",\n      \"method\": \"Gel shift assay (EMSA), luciferase reporter assay, in silico E-box analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — EMSA and reporter assay for direct binding, single lab\",\n      \"pmids\": [\"25475555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIB3 binds the WR domain of TWIST1 and stabilizes it by inhibiting ubiquitination; disruption of the TRIB3-TWIST1 interaction by a peptide analogue promotes TWIST1 degradation and reverses ATRA resistance in APL.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, peptide disruption of protein-protein interaction, in vivo APL models\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction mapped to WR domain, ubiquitination assay, in vivo rescue\",\n      \"pmids\": [\"31235507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP4 binds to, deubiquitinates, and stabilizes TWIST1 protein, promoting lung cancer stemness; silencing USP4 leads to TWIST1 degradation and loss of cancer stem cell properties, rescuable by TWIST1 re-expression.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, knockdown/overexpression, stem cell assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical deubiquitination assay, single lab\",\n      \"pmids\": [\"32549341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP18 interacts with TWIST1, removes its ubiquitin chains, and stabilizes it to promote EMT and glioblastoma invasion; TWIST1 re-expression fully rescues USP18-depletion phenotypes.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, shRNA knockdown, in vivo tumor model\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct deubiquitination assay and rescue experiments, single lab\",\n      \"pmids\": [\"32368392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CBX7 binds the E-box sequence to block TWIST1 from binding its target DNA, rendering TWIST1 transcriptionally nonfunctional in secondary ovarian cancer cells; deletion of CBX7 reactivates TWIST1-induced transcription and mesenchymal transformation.\",\n      \"method\": \"Chromatin binding assay, E-box competition assay, CBX7 knockout, in vivo tumorigenicity\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct E-box competition demonstrated, in vivo rescue, single lab\",\n      \"pmids\": [\"32205869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Mutant CFTR intrinsically triggers EMT through TWIST1; CFTR modulator drugs reverse the CF EMT phenotype by restoring functional CFTR and reducing TWIST1-mediated EMT.\",\n      \"method\": \"CFTR-mutant cell lines and native tissue, EMT marker expression, drug rescue with CFTR modulators\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic link established with rescue experiments, multiple cellular models\",\n      \"pmids\": [\"33106471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"G3BP2 promotes TWIST1 ubiquitination and proteasomal degradation; α-parvin binding to G3BP2 prevents this interaction, thereby stabilizing TWIST1 and promoting breast cancer metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, mutagenesis of α-parvin G3BP2-binding site, in vivo tumor progression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding mapped by mutagenesis, ubiquitination assay, in vivo validation\",\n      \"pmids\": [\"30804457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TWIST1 and chromatin regulators CHD7, CHD8, and WHSC1 form a TWIST1-chromatin regulatory module (TWIST1-CRM) in neural crest cells; perturbation of any core member causes abnormal NCC differentiation and craniofacial defects. TWIST1-CRM represses neural stem cell programs at low activity and commits NCCs to ectomesenchyme at high activity.\",\n      \"method\": \"BioID proximity labeling, network propagation analysis, combinatorial knockdown in cell models and mouse embryos\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — unbiased proximity proteomics plus multiple loss-of-function models in vivo\",\n      \"pmids\": [\"33554859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Twist1 in macrophages directly activates galectin-3 transcription and regulates M2 macrophage polarization; Twist1 also controls macrophage chemotaxis partly through the CCL2/CCR2 axis. Macrophage-specific Twist1 ablation reduces renal fibrosis.\",\n      \"method\": \"Conditional macrophage-specific Twist1 knockout, ChIP (galectin-3 promoter), cytokine secretion assays, UUO model\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding by ChIP, conditional KO with mechanistic readout, in vivo model\",\n      \"pmids\": [\"35182235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TWIST1 acetylation at K73/76 determines its co-activator versus co-repressor function: non-acetylated TWIST1-K73/76 recruits NuRD complex to repress epithelial target genes, while diacetylated TWIST1-acK73/76 binds BRD8 (a TIP60-Com component) to recruit TIP60-Com and activate mesenchymal genes and MYC. Knockdown of BRD8 abolishes TWIST1/TIP60-Com interaction and reduces TWIST1-activated gene expression.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, acetylation-mimetic/dead mutants, BRD8 knockdown, RNA-seq\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — acetylation-dependent complex switching demonstrated by Co-IP, ChIP-seq, mutagenesis, and functional RNA-seq\",\n      \"pmids\": [\"37680145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDK1 phosphorylates USP29, which activates USP29's deubiquitinase activity toward TWIST1, thereby stabilizing TWIST1 and promoting EMT, chemoresistance, and metastasis in TNBC; CDK1 inhibition destabilizes TWIST1.\",\n      \"method\": \"In vitro kinase assay, ubiquitination assay, Co-immunoprecipitation, CDK1 genetic ablation, pharmacological inhibition\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted kinase assay plus deubiquitination assay, genetic and pharmacological inhibition in vivo\",\n      \"pmids\": [\"36782089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP13 directly interacts with TWIST1, cleaves K48-linked polyubiquitin chains added by FBXL14, and stabilizes TWIST1 protein; TWIST1 in turn transcriptionally represses USP13, forming a negative feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, GST-pulldown, ubiquitination assay, ChIP and luciferase reporter\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction by GST-pulldown and Co-IP, ubiquitin linkage specificity assay, transcriptional feedback by ChIP\",\n      \"pmids\": [\"36732432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FBXO3 stabilizes USP4 by disrupting the interaction between USP4 and DNPEP (aspartyl aminopeptidase), preventing DNPEP-mediated USP4 degradation; stabilized USP4 in turn deubiquitinates and stabilizes TWIST1 to promote breast cancer metastasis. PI3K-p110αH1047R facilitates FBXO3 phosphorylation and stabilization via ERK1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, FBXO3 mutagenesis (E3-dead), in vivo mouse metastasis assay\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis of E3-ligase-dead construct, direct interaction mapping, in vivo validation\",\n      \"pmids\": [\"38134227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TWIST1 directly binds to Bmi1 promoter E-box sequences and activates Bmi1 expression, linking EMT induction to cancer stemness via chromatin remodeling.\",\n      \"method\": \"Chromatin immunoprecipitation, reporter assays, head and neck cancer patient samples\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assays, patient sample correlation, single lab\",\n      \"pmids\": [\"21919891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TWIST1 directly binds E-box sequences in the promoters of Tbx20, Cdh11, Sema3C, Rab39b, and Gadd45a in developing heart valve endocardial cushion cells, regulating proliferation and migration of valve mesenchymal cells.\",\n      \"method\": \"ChIP assay, candidate gene and global gene profiling, evolutionarily conserved E-box analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo ChIP confirming direct binding to multiple target promoters in tissue\",\n      \"pmids\": [\"22242143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TWIST1 directly binds the promoters of Cyclin E1, E2F1, and c-Myc at canonical E-box motifs to regulate cell cycle progression at G1/S, promoting keratinocyte proliferation and skin tumor initiation.\",\n      \"method\": \"ChIP, conditional Twist1 KO in keratinocytes, cell cycle analysis, Western blot\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP evidence for direct binding plus loss-of-function with defined cell cycle phenotype\",\n      \"pmids\": [\"26013710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TWIST1 directly binds the promoters of Ddr2, Pcolce, and Tgfbi in cranial mesoderm, and these targets regulate extracellular matrix/cell-matrix interactions required for mesenchymal maintenance. ChIP-seq in an in vitro TWIST1-dependent mesenchymal model identified genome-wide TWIST1 binding sites.\",\n      \"method\": \"ChIP-seq, ChIP-PCR on embryonic tissues, luciferase reporter assays, Twist1 conditional KO\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP-seq plus validation by ChIP-PCR in vivo and reporter assay, conditional KO phenotype\",\n      \"pmids\": [\"27546376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TWIST1 directly binds the FoxM1 promoter at an E-box motif and recruits p300 to induce FoxM1 mRNA transcription, thereby promoting gastric cancer cell proliferation.\",\n      \"method\": \"ChIP, reporter assay, knockdown/overexpression of Twist1 and FoxM1\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay for direct binding and p300 co-recruitment, single lab\",\n      \"pmids\": [\"24204899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TWIST1 drives smooth muscle cell proliferation in pulmonary hypertension by promoting proteasomal degradation of GATA-6; loss of GATA-6 reduces BMPR2 expression because GATA-6 directly binds the BMPR2 promoter. SMC-specific Twist1 deletion attenuates PH and vascular remodeling.\",\n      \"method\": \"SMC-specific Twist1 conditional KO, mass spectrometry, Co-IP, ChIP, in vitro SMC proliferation\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO in two animal models, ChIP for GATA-6/BMPR2, Co-IP, MS identification of interactors\",\n      \"pmids\": [\"32692930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TWIST1 directly induces expression of discoidin domain receptor 2 (DDR2) in ovarian cancer cells, and DDR2 stabilizes SNAIL1 to sustain the mesenchymal phenotype and enable peritoneal metastasis.\",\n      \"method\": \"shRNA knockdown, overexpression, in vivo metastasis model, patient-derived tumor cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined metastatic phenotype, patient correlation, single lab\",\n      \"pmids\": [\"29348456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TWIST1 directly binds to the miR-584 genomic locus to activate its transcription (confirmed by ChIP), and miR-584 targets TUSC2 to promote resistance to apoptosis in thyroid cancer cells.\",\n      \"method\": \"ChIP, miRNome profiling, luciferase assay, overexpression/anti-miR experiments\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct TWIST1 binding to miR-584 by ChIP, functional rescue experiments, single lab\",\n      \"pmids\": [\"27661106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TWIST1 expression in Th1 effector memory cells is induced by NF-κB, NFAT, and IL-12/STAT4 signaling, and TWIST1 in turn limits expression of IFN-γ, IL-2, and TNF-α to autoregulate Th1-mediated immunopathology.\",\n      \"method\": \"T cell stimulation assays, transcription factor inhibition (dominant negatives and pharmacological), adoptive transfer models of delayed-type hypersensitivity and antigen-induced arthritis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple transcription factor pathway inhibition, in vivo mouse models with defined phenotype\",\n      \"pmids\": [\"18663125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TWIST1 dissemination from primary mammary epithelium requires E-cadherin; Twist1 expression induces changes in extracellular matrix and cell-matrix adhesion genes (not cell-cell adhesion genes), and E-cadherin knockdown strongly inhibits Twist1-induced single-cell dissemination.\",\n      \"method\": \"3D mammary organoid culture, live imaging, RNA-seq transcriptional profiling, E-cadherin knockdown, conditional mouse model\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, unexpected mechanistic finding (E-cadherin required for dissemination), well-controlled genetic models\",\n      \"pmids\": [\"24590176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TWIST1 (H-Twist) overexpression inhibits the ARF/p53 apoptotic pathway in N-Myc-amplified neuroblastoma, enabling oncogenic cooperation between TWIST1 and N-Myc to cause cell transformation and circumvent p53-dependent apoptosis.\",\n      \"method\": \"Pangenomic cDNA microarray, functional cell transformation assays, apoptosis assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — microarray identification combined with functional transformation assays, single lab\",\n      \"pmids\": [\"15607966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Enhancers eTw-5, eTw-6, and eTw-7 within the TWIST1-HDAC9 locus physically interact with the Twist1 promoter (by 4C-seq) in limb bud and branchial arch; LMX1B and TFAP2 bind these enhancers to modulate TWIST1 transcription. CRISPR deletion of eTw5-7 reduces Twist1 expression and causes pre-axial polydactyly.\",\n      \"method\": \"4C-seq, ChIP-seq (p300, H3K27ac), CRISPR/Cas9 enhancer deletion, zebrafish/mouse enhancer assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — 4C-seq for physical interaction, CRISPR deletion producing phenotype, transcription factor binding identified\",\n      \"pmids\": [\"30372441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TWIST1 is highly expressed in IPF myofibroblasts with selectively increased chromatin accessibility at the TWIST1 locus; Twist1 overexpression in COL1A2-expressing fibroblasts increases collagen synthesis and upregulates fibrosis-related gene programs.\",\n      \"method\": \"Single-nucleus ATAC-seq, scRNA-seq integration, Twist1 overexpression in bleomycin-injured Cre-ER mice, RNA-seq\",\n      \"journal\": \"European respiratory journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — single-nucleus chromatin accessibility plus in vivo overexpression mouse model with transcriptomic readout\",\n      \"pmids\": [\"37142338\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TWIST1 is a bHLH transcription factor that forms homo- and hetero-dimers regulated by phosphorylation (via PKA, AURKA, CDK1) and acetylation (at K73/76), determining whether it recruits the NuRD co-repressor complex to silence epithelial genes or the TIP60-Com co-activator complex to activate mesenchymal and proliferative genes; its protein stability is controlled by multiple deubiquitinases (USP4, USP13, USP18, USP29) and E3 ligase complexes (FBXL14, Pirh2), and its activity promotes EMT, cancer metastasis, vascular remodeling, fibrosis, and immune regulation through direct transcriptional control of E-cadherin, VE-cadherin, Bmi1, FoxM1, CCL2, Tie2, GATA-6/BMPR2, and many other targets.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TWIST1 is a basic helix-loop-helix (bHLH) transcription factor that functions as a master regulator of epithelial-mesenchymal transition (EMT), mesenchymal cell fate, and tissue remodeling by forming context-dependent homo- or heterodimers whose partner choice and transcriptional output are controlled by phosphorylation and acetylation. Non-acetylated TWIST1 recruits the NuRD co-repressor complex to silence epithelial genes such as E-cadherin and FOXA1, whereas diacetylation at K73/K76 switches its interaction to the TIP60-Com co-activator complex via BRD8, enabling activation of mesenchymal and proliferative targets including MYC, Bmi1, FoxM1, and Tie2 [PMID:37680145, PMID:21876555, PMID:27524420, PMID:24204899]. Protein stability is tightly regulated by multiple deubiquitinases (USP4, USP13, USP18, USP29) and E3 ligase pathways (FBXL14, Pirh2, G3BP2), with upstream kinases including PKA, Aurora A, and CDK1 controlling dimer composition, ubiquitin susceptibility, and transcriptional potency [PMID:15735646, PMID:28167680, PMID:36782089, PMID:36732432, PMID:30131448]. Beyond its canonical role in cancer metastasis and stemness, TWIST1 directs neural crest cell differentiation through a chromatin regulatory module containing CHD7/CHD8/WHSC1, regulates vascular integrity and angiogenesis through the angiopoietin-Tie2 axis, drives tissue fibrosis in lung and skin, and limits Th1 cytokine production to restrain immunopathology [PMID:33554859, PMID:27281171, PMID:37142338, PMID:18663125].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that TWIST1 has oncogenic activity beyond EMT: TWIST1 was shown to cooperate with N-Myc by suppressing the ARF/p53 apoptotic pathway, revealing a pro-survival transcriptional function.\",\n      \"evidence\": \"cDNA microarray and functional transformation/apoptosis assays in neuroblastoma cells\",\n      \"pmids\": [\"15607966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ARF pathway suppression not molecularly defined\", \"No direct promoter binding to ARF pathway genes shown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolving how TWIST1 dimer partner choice is determined: PKA-mediated phosphorylation of helix I residues was shown to regulate whether TWIST1 homodimerizes or heterodimerizes with HAND2, and Saethre-Chotzen syndrome mutations disrupt this phosphoregulation.\",\n      \"evidence\": \"In vivo phosphorylation assays, mouse limb genetics, domain mutagenesis\",\n      \"pmids\": [\"15735646\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of phosphorylated versus unphosphorylated dimers not resolved\", \"Full spectrum of phosphosites controlling partner choice not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extending TWIST1 function to immune regulation: TWIST1 was found to be induced in Th1 effector memory cells via NF-κB/NFAT/STAT4 and to limit IFN-γ, IL-2, and TNF-α expression, establishing a negative feedback loop restraining immunopathology.\",\n      \"evidence\": \"T cell stimulation, transcription factor inhibition, adoptive transfer arthritis models\",\n      \"pmids\": [\"18663125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct promoter binding to cytokine loci not demonstrated by ChIP\", \"Mechanism of transcriptional repression in T cells unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying the NuRD complex as TWIST1's repressive effector: TWIST1 was shown to recruit NuRD to the E-cadherin promoter to repress transcription, and to directly activate Bmi1 via E-box binding, linking EMT to stemness.\",\n      \"evidence\": \"ChIP, reporter assays, biochemical characterization of bHLH domain\",\n      \"pmids\": [\"21876555\", \"21919891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which NuRD subunits directly contact TWIST1 not identified\", \"Whether NuRD recruitment requires specific post-translational modification state was unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealing TWIST1's paracrine and developmental regulatory roles: TWIST1 was shown to induce CCL2 to recruit pro-angiogenic macrophages, to interact with SOX10 via its Twist-box to repress PHOX2B and control neural crest fate, and to recruit p300 to the FoxM1 promoter for proliferative gene activation.\",\n      \"evidence\": \"In vivo macrophage depletion/rescue, conditional mouse KO with promoter-reporter assays, ChIP\",\n      \"pmids\": [\"23329645\", \"23555309\", \"24204899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CCL2 induction is direct or indirect not fully resolved\", \"Structural basis of SOX10-Twist-box interaction not determined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing TWIST1 protein stability as a regulatory node: p62/SQSTM1 was shown to stabilize TWIST1 by blocking both proteasomal and autophagosomal degradation, while wild-type p53 recruited Pirh2 to ubiquitinate TWIST1, and E-cadherin was paradoxically shown to be required for TWIST1-induced cell dissemination.\",\n      \"evidence\": \"Co-IP, autophagy-deficient models, ubiquitination assays, 3D organoid live imaging\",\n      \"pmids\": [\"24927592\", \"30131448\", \"24590176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which ubiquitin linkage types are added by Pirh2 not defined\", \"How E-cadherin mechanistically promotes dissemination despite being a TWIST1-repressed target remains unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrating TWIST1's EMT-independent roles in stem cell maintenance and cell cycle: conditional Twist1 KO in skin depleted keratinocyte stem cells and blocked tumor initiation in a p53-dependent manner, while ChIP confirmed direct binding to Cyclin E1, E2F1, and c-Myc promoters.\",\n      \"evidence\": \"Conditional KO at multiple carcinogenesis stages, flow cytometry, ChIP, cell cycle analysis\",\n      \"pmids\": [\"25575080\", \"26013710\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether stem cell depletion is cell-autonomous or requires niche signals not fully resolved\", \"Relative contribution of each cell cycle target not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defining TWIST1's vascular and fibrotic functions: Ser42 phosphorylation was required for Tie2 regulation and angiogenesis, TGFβ-induced ID proteins shifted TWIST1 toward homodimers to drive fibroblast activation and fibrosis, and EC-specific TWIST1 deletion reduced atherosclerosis.\",\n      \"evidence\": \"Phospho-mutant constructs, endothelial and fibroblast conditional KOs, bleomycin fibrosis models, ChIP-seq\",\n      \"pmids\": [\"27281171\", \"27113414\", \"27245171\", \"27546376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for Ser42 phosphorylation not identified\", \"Whether homodimer-specific target gene sets differ in fibroblasts versus endothelial cells not determined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealing a TWIST1-AURKA mutual stabilization loop: Aurora kinase A phosphorylation of TWIST1 at three sites inhibited ubiquitination and favored homodimerization, while TWIST1 reciprocally prevented AURKA degradation.\",\n      \"evidence\": \"In vitro kinase assay, ubiquitination assay, phospho-dead/mimic mutants, in vivo tumor formation\",\n      \"pmids\": [\"28167680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AURKA phosphorylation sites overlap with PKA sites not clarified\", \"Structural mechanism of phosphorylation-dependent ubiquitination resistance unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanding the regulatory landscape of TWIST1: upstream enhancers eTw-5/6/7 were shown to physically contact the TWIST1 promoter and be bound by LMX1B/TFAP2, TWIST1 activated CUL2/circ-10720 for EMT, and E2A heterodimer stability was shown to differ from homodimer stability.\",\n      \"evidence\": \"4C-seq, CRISPR enhancer deletion causing polydactyly, ChIP, dimer-specific degradation assays\",\n      \"pmids\": [\"30372441\", \"29844124\", \"28851812\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Complete enhancer logic for tissue-specific TWIST1 expression not mapped\", \"Functional significance of circular RNA versus mRNA output ratio unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying multiple deubiquitinases and adaptor proteins controlling TWIST1 turnover: USP4, USP18, and the G3BP2/α-parvin axis were each shown to regulate TWIST1 ubiquitination status, and TWIST1 was shown to promote pulmonary hypertension by degrading GATA-6.\",\n      \"evidence\": \"Co-IP and deubiquitination assays, conditional SMC-specific Twist1 KO, ubiquitination assays with domain mapping\",\n      \"pmids\": [\"32549341\", \"32368392\", \"30804457\", \"32692930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of individual DUBs in a single tissue context not compared\", \"Whether USP4 and USP18 act on the same or different ubiquitin chain types on TWIST1 not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying a TWIST1-chromatin regulatory module (CRM) in neural crest: BioID proximity labeling revealed CHD7, CHD8, and WHSC1 as core TWIST1 partners that collectively control NCC differentiation and craniofacial morphogenesis.\",\n      \"evidence\": \"BioID proximity proteomics, combinatorial knockdown in cells and mouse embryos\",\n      \"pmids\": [\"33554859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TWIST1-CRM uses the same acetylation switch as NuRD/TIP60-Com not tested\", \"Direct versus indirect interactions within the CRM not fully resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolving the acetylation switch governing TWIST1 co-factor choice: K73/K76 diacetylation was shown to switch TWIST1 from NuRD-mediated repression to BRD8/TIP60-Com-mediated activation, and CDK1-phosphorylated USP29 was identified as another stabilizing DUB, while FBXL14 was identified as the E3 ligase counteracted by USP13.\",\n      \"evidence\": \"Acetylation-mimetic/dead mutants with ChIP-seq and RNA-seq, in vitro kinase and deubiquitination assays, GST-pulldown\",\n      \"pmids\": [\"37680145\", \"36782089\", \"36732432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetyltransferase responsible for K73/K76 acetylation not identified\", \"How the acetylation switch integrates with phosphorylation-dependent dimer choice is unknown\", \"Whether the NuRD-to-TIP60 switch operates in non-cancer developmental contexts not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The acetyltransferase writing K73/K76, the structural basis for acetylation-dependent cofactor switching, the integration of phosphorylation and acetylation codes on a single TWIST1 molecule, and the tissue-specific hierarchy among multiple DUBs remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of K73/K76 acetyltransferase unknown\", \"No structural model of TWIST1 bound to NuRD versus TIP60-Com\", \"Relative hierarchy of USP4/USP13/USP18/USP29 in physiological tissues not established\", \"How enhancer-level and post-translational regulation are coordinated across tissues remains open\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 8, 29, 33, 35, 37]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 8, 9, 10, 33, 34, 35, 36]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 8, 29, 36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 8, 29, 33, 35, 36, 37]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [27, 29]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 7, 27, 34, 44]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 13, 14, 38]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [41, 28]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 16, 18, 22, 23, 30, 31]}\n    ],\n    \"complexes\": [\n      \"NuRD complex\",\n      \"TIP60-Com (NuA4)\",\n      \"TWIST1-CRM (CHD7/CHD8/WHSC1)\"\n    ],\n    \"partners\": [\n      \"E2A\",\n      \"HAND2\",\n      \"SOX10\",\n      \"BRD8\",\n      \"AURKA\",\n      \"USP4\",\n      \"USP29\",\n      \"TRIB3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}