{"gene":"KLF10","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1997,"finding":"Overexpression of TIEG1/KLF10 in TGF-β-sensitive PANC1 pancreatic epithelial cells is sufficient to induce apoptosis, establishing KLF10 as a downstream effector linking TGF-β signaling to cell death.","method":"Stable overexpression in PANC1 cells with functional apoptosis readout","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean overexpression with defined apoptotic phenotype, single lab but clearly described functional consequence","pmids":["9153278"],"is_preprint":false},{"year":1999,"finding":"TIEG1/KLF10 contains three conserved transcriptional repressor domains (R1: 10 aa, R2: 12 aa, R3: ~80 aa) outside the zinc finger DNA-binding domain that are functionally conserved between TIEG1 and TIEG2, as defined by extensive mutagenesis and GAL4-based transcriptional assays.","method":"Extensive mutagenesis combined with GAL4-based transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis with functional reporter assays, multiple domains defined with orthogonal validation","pmids":["10506214"],"is_preprint":false},{"year":1999,"finding":"TIEG1/KLF10-induced apoptosis in Hep 3B cells proceeds via a mechanism involving increased reactive oxygen species generation and loss of mitochondrial membrane potential, preceding caspase-3 activation and glutathione depletion; the antioxidant trolox blocks both ROS and apoptosis.","method":"ROS measurement, mitochondrial membrane potential assay, caspase activity assay, antioxidant rescue experiment in Hep 3B cells","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal mechanistic assays (ROS, mitochondrial potential, caspase, antioxidant rescue) in a single rigorous study establishing the apoptotic sequence","pmids":["10573529"],"is_preprint":false},{"year":2000,"finding":"Stable overexpression of TIEG1/KLF10 in human osteosarcoma MG-63 cells mimics TGF-β action: increased alkaline phosphatase activity, decreased osteocalcin mRNA/protein, and decreased cell proliferation, without additive effect upon TGF-β treatment.","method":"Stable transfection of TIEG cDNA in MG-63 cells with gene expression and proliferation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean overexpression model with multiple functional readouts, single lab","pmids":["10816551"],"is_preprint":false},{"year":2003,"finding":"The zinc finger domain of TIEG1/KLF10 binds a GT-rich consensus core sequence (5'-GGTGTG-3') as established by iterative nitrocellulose filter-binding selection from a random oligonucleotide library and mutational analysis.","method":"In vitro selection from random oligonucleotide library (SELEX-like), nitrocellulose filter binding, mutational analysis of binding site","journal":"DNA and cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical binding assay with mutagenesis identifying necessary core sequence, single lab","pmids":["12804117"],"is_preprint":false},{"year":2003,"finding":"Nitric oxide (NO) upregulates TIEG1/KLF10 mRNA in human IMR-90 fibroblasts by stabilizing the transcript (6-fold increase in half-life), independently of TGF-β, as shown by anti-TGF-β antibody blocking and mRNA half-life measurements.","method":"Northern blotting, anti-TGF-β antibody neutralization, mRNA stability assay","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal approaches (neutralization and half-life measurement), single lab","pmids":["12788480"],"is_preprint":false},{"year":2004,"finding":"TIEG1/KLF10 overexpression in oligodendroglial OLI-neu cells induces apoptosis by repressing Bcl-XL expression and enhancing SMAD-dependent TGF-β signaling, while reducing SMAD7 promoter activity.","method":"Overexpression in OLI-neu cells, apoptosis ELISA, DNA fragmentation, caspase-3 assay, luciferase reporter for SMAD7 promoter","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal apoptosis assays plus promoter reporter, single lab","pmids":["14743447"],"is_preprint":false},{"year":2005,"finding":"TIEG1/KLF10 knockout osteoblasts are defective in BMP2-induced mineralization in vitro and show decreased RANKL and increased OPG expression, resulting in impaired support of osteoclast differentiation.","method":"TIEG1 knockout mouse calvarial osteoblast culture, BMP2 treatment, mineralization nodule assay, osteoclast co-culture with RANKL/M-CSF rescue","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with multiple cellular phenotypes and partial rescue experiments, replicated across multiple assays in one rigorous study","pmids":["15657444"],"is_preprint":false},{"year":2007,"finding":"BMP2 opposes Shh-mediated proliferation in cerebellar granule neuron precursors by inducing TIEG1/KLF10, which occupies Sp1 sites in the N-myc promoter and blocks N-myc expression, leading to cell cycle arrest.","method":"Chromatin occupancy at Nmyc promoter, ectopic TIEG1 expression in cerebellar granule neuron precursors, cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter occupancy plus functional overexpression in primary cells, single lab","pmids":["17951258"],"is_preprint":false},{"year":2007,"finding":"TIEG1/KLF10 induces apoptosis through the mitochondrial pathway in K562 leukemia cells, involving Bax and Bim up-regulation, Bcl-2 and Bcl-XL down-regulation, cytochrome c release, caspase-3 activation, and mitochondrial membrane potential disruption.","method":"TIEG1 overexpression in K562 cells, Western blotting for Bcl-2 family members, cytochrome c release assay, caspase-3 activity, mitochondrial membrane potential measurement","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic markers of mitochondrial apoptosis measured in parallel, single lab","pmids":["17659279"],"is_preprint":false},{"year":2008,"finding":"The E3 ubiquitin ligase Itch associates with TIEG1/KLF10 and promotes its non-proteolytic K63-linked ubiquitination; this cooperates with TIEG1 to induce Foxp3 expression in T cells, and TGF-β-converted Tregs from TIEG1-deficient mice fail to suppress airway inflammation.","method":"Co-immunoprecipitation, ubiquitination assay, Itch-/- and TIEG1-/- mouse T cell functional studies, in vivo airway inflammation model","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, multiple KO mouse models, in vivo functional rescue, published in high-tier journal","pmids":["18278048"],"is_preprint":false},{"year":2008,"finding":"KLF10 directly transactivates both the TGF-β1 and Foxp3 promoters in CD4+ T cells in response to TGF-β1, forming a positive feedback loop; KLF10-/- CD4+CD25- T cells show enhanced Th1/Th2 differentiation and cannot be suppressed by wild-type Tregs, while KLF10-/- Tregs have reduced TGF-β1 production and suppressor function rescued by exogenous TGF-β1.","method":"KLF10 KO mouse CD4+ T cell functional studies, promoter transactivation assays, Th1/Th2 cytokine profiling, atherosclerosis model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO model, promoter transactivation, multiple functional readouts and in vivo atherosclerosis model, comprehensive mechanistic characterization","pmids":["19602726"],"is_preprint":false},{"year":2008,"finding":"KLF10 is a VHL target gene; KLF10 transactivates the TGFBI (BIGH3) promoter as assessed by luciferase reporter assay, establishing KLF10 as an intermediate between VHL status and ECM gene expression in clear cell carcinoma.","method":"Expression arrays, luciferase reporter assay of TGFBI promoter with KLF10 co-transfection, cell lines with different VHL status","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase reporter with co-transfection; VHL control established via expression arrays, single lab","pmids":["18359287"],"is_preprint":false},{"year":2010,"finding":"TIEG1/KLF10 directly binds the Bmal1 promoter through two juxtaposed GC boxes near the transcription initiation site and represses Bmal1 transcription; siRNA knockdown of TIEG1 causes period shortening in cellular bioluminescence rhythms driven by Bmal1-luciferase and Per2-luciferase reporters.","method":"In vitro transcription assay, luciferase reporter with mutational analysis, siRNA knockdown, real-time bioluminescence circadian assay","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding demonstrated, promoter mutational analysis, live-cell circadian reporter rescue, multiple orthogonal methods in one study","pmids":["20070857"],"is_preprint":false},{"year":2010,"finding":"KLF10 displays circadian expression in mouse liver driven by CLOCK-BMAL1; the Klf10 promoter recruits BMAL1 and is transactivated by CLOCK-BMAL1 through a conserved E-box. KLF10 deficiency in liver causes postprandial/fasting hyperglycemia with upregulation of Pepck; KLF10 directly represses the Pepck promoter.","method":"KLF10 KO mice, Bmal1 KO mice, chromatin immunoprecipitation of BMAL1 at Klf10 promoter, liver transcriptome profiling, luciferase reporter for Pepck promoter, hepatic glucose production assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO models, ChIP, promoter luciferase, transcriptomics, and metabolic phenotyping, multiple orthogonal methods","pmids":["20385766"],"is_preprint":false},{"year":2010,"finding":"JARID1B/KDM5B is a corepressor of TIEG1/KLF10: the repression domains of TIEG1 bind the C-terminus of JARID1B. JARID1B overexpression augments TIEG1-mediated repression of Smad7; JARID1B knockdown increases Smad7 mRNA, indicating TIEG1 represses transcription through histone H3K4 demethylation.","method":"Co-immunoprecipitation (TIEG1–JARID1B), domain mapping, Smad7 reporter assay with JARID1B overexpression/knockdown","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping and functional reporter, single lab","pmids":["20863814"],"is_preprint":false},{"year":2011,"finding":"IL-6 activates Tyk2, which phosphorylates TIEG1/KLF10 at Tyr179, promoting non-canonical K27-linked polyubiquitination that inhibits TIEG1 nuclear translocation and thereby abrogates TGF-β-induced Treg development.","method":"Phosphorylation assays, ubiquitination assays, nuclear fractionation, functional Treg development assay, TRAMP-C2 tumor model in TIEG1-/- mice","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple biochemical assays (phosphorylation, ubiquitination, fractionation) plus in vivo tumor model, comprehensive mechanistic pathway","pmids":["21471442"],"is_preprint":false},{"year":2011,"finding":"TIEG1/KLF10 directly binds to and activates the Runx2 promoter (via its zinc finger domain) and physically associates with Runx2 protein to co-activate Runx2 transcriptional activity; TGF-β1 and BMP2 induction of Runx2 requires TIEG1 expression.","method":"Transient transfection with promoter deletion constructs, chromatin immunoprecipitation, co-immunoprecipitation, adenoviral Runx2 rescue in KO osteoblasts","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, Co-IP, promoter deletion mutant analysis, and KO rescue experiments in primary cells","pmids":["21559363"],"is_preprint":false},{"year":2011,"finding":"TIEG1/KLF10 suppresses breast cancer cell invasion and mammary tumorigenesis by directly binding to the EGFR promoter at Sp1 sites, recruiting HDAC1, suppressing histone acetylation, and thereby inhibiting EGFR transcription.","method":"TIEG1 overexpression/knockdown, chromatin immunoprecipitation, co-immunoprecipitation of TIEG1-HDAC1 complex, EGFR promoter binding, invasion assay, xenograft model","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP for complex, ChIP at EGFR promoter, overexpression/knockdown with invasion and in vivo xenograft, multiple orthogonal methods","pmids":["22025675"],"is_preprint":false},{"year":2011,"finding":"Klf10 directly modulates transcription of BI-1 (Bax inhibitor-1) by binding to the BI-1 promoter, as confirmed by ChIP-chip, EMSA, and BI-1 promoter mutation that abolishes Klf10-mediated repression; reduced BI-1 increases cytosolic Ca2+ and induces apoptosis in estrogen-responding breast cancer cells.","method":"ChIP-chip, EMSA, BI-1 promoter luciferase with binding site mutation, si-KLF10 rescue, intracellular Ca2+ measurement","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP-chip plus EMSA plus promoter mutation plus Ca2+ functional readout, multiple orthogonal methods","pmids":["21262377"],"is_preprint":false},{"year":2012,"finding":"KLF10 dose-dependently activates p21WAF1/CIP1 transcription independently of p53 and Sp1 binding sites, and KLF10-deficient mice exhibit increased susceptibility to skin tumorigenesis after DMBA/TPA treatment.","method":"KLF10 KO mouse tumorigenesis model, p21 promoter luciferase assay with deletion/mutation, colony formation assay after H-Ras transfection","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO in vivo model plus promoter reporter, but single lab","pmids":["22349513"],"is_preprint":false},{"year":2013,"finding":"KLF10 stability is regulated by RAF-1-mediated phosphorylation at Thr93 and subsequent interaction with the prolyl isomerase PIN1 (identified by yeast two-hybrid); PIN1 binding (phosphorylation-dependent, via the pThr93-Pro motif) promotes KLF10 protein degradation.","method":"In vitro and in vivo phosphorylation assays, yeast two-hybrid screening, site-directed mutagenesis of Thr93, protein-protein interaction assays, cycloheximide chase, in vitro kinase assay with RAF-1","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay, yeast two-hybrid, mutagenesis, and cycloheximide chase providing multiple lines of evidence for the mechanism","pmids":["23994618"],"is_preprint":false},{"year":2013,"finding":"KLF10 represses FGFR1 promoter activity in myoblasts by binding to the proximal Sp1 binding site of the FGFR1 promoter, competing with Sp1, thereby reducing myoblast proliferation by 86%.","method":"Southwestern blot, electromobility shift assay (EMSA), chromatin immunoprecipitation, FGFR1 promoter luciferase in myoblasts and Drosophila SL2 cells, cell proliferation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct DNA binding shown by EMSA and ChIP, functional promoter assay, proliferation phenotype, multiple orthogonal methods","pmids":["23569208"],"is_preprint":false},{"year":2014,"finding":"KLF10 directly binds to the TGF-βRII promoter in CD8+ T cells, activating its transcription; KLF10-deficient CD8+ T cells show reduced TGF-βRII surface expression and attenuated Smad2 phosphorylation after TGF-β1 stimulation.","method":"Chromatin immunoprecipitation, TGF-βRII promoter binding assay, KLF10-/- mouse CD8+ T cell phenotyping, flow cytometry for TGF-βRII, phospho-Smad2 measurement, in vivo viral infection model","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP at TGF-βRII promoter plus KO mouse functional studies plus in vivo viral model, replicated in multiple contexts","pmids":["25472963"],"is_preprint":false},{"year":2014,"finding":"KLF10 integrates antagonistic epigenetic signals at the FOXP3 promoter: an NH2-terminal Sin3-interacting repressor domain limits KLF10 activation, while inactivation of this domain enables KLF10 to physically associate with the histone acetyltransferase PCAF to induce FOXP3 gene transcription.","method":"Chromatin immunoprecipitation, genome-integrated reporter assay, functional domain KLF10 mutant proteins, Co-IP with PCAF and Sin3-HDAC complex, primary murine lymphocyte validation","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mutagenesis, Co-IP with two opposing complexes, ChIP, genome-integrated reporter, and primary cell validation","pmids":["24944246"],"is_preprint":false},{"year":2015,"finding":"KLF10 directly binds to the TGF-βRII promoter in macrophages, enhancing its transcription through histone H3 acetylation; KLF10-deficient macrophages show reduced TGF-βRII expression, attenuated Smad2 phosphorylation, and a pro-inflammatory cytokine profile (increased TNF-α, decreased IL-10).","method":"Chromatin immunoprecipitation, KLF10-/- mouse bone marrow-derived macrophage studies, H3 acetylation assay at TGF-βRII promoter, cytokine ELISA, adoptive transfer of KO macrophages","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP with histone mark, KO macrophages, cytokine profiling, and adoptive transfer model","pmids":["26472224"],"is_preprint":false},{"year":2015,"finding":"KLF10 transcriptionally activates the SEI-1 promoter and induces SEI-1 protein expression in pancreatic carcinoma cells, subsequently increasing p21Cip1 expression; KLF10-deficient mice show decreased pancreatic islet mass with nuclear accumulation of p21Cip1.","method":"ChIP-chip identification of SEI-1 as KLF10 target, luciferase promoter assay, KLF10 KO mouse islet histology","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-chip, promoter reporter, and KO mouse phenotype, but limited functional rescue data, single lab","pmids":["25578559"],"is_preprint":false},{"year":2016,"finding":"TIEG1/KLF10 directly binds to and activates the Osterix promoter (via its zinc finger DNA-binding domain) in osteoblasts; TIEG1 is required for induction of Osterix by TGF-β1 and BMP2.","method":"Transient transfection with Osterix promoter constructs, chromatin immunoprecipitation, shRNA and CRISPR knockdown of TIEG1, KO osteoblast complementation","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, promoter deletion analysis, multiple KD strategies and KO rescue in primary osteoblasts","pmids":["26801561"],"is_preprint":false},{"year":2017,"finding":"KLF10 suppresses TGF-β-induced EMT by occupying GC-rich sequences in the SLUG/SNAI2 promoter, recruiting HDAC1, and removing activating histone acetylation marks to repress SLUG transcription.","method":"KLF10 depletion (siRNA/shRNA), chromatin immunoprecipitation at SLUG promoter, histone acetylation assay, EMT marker panel, lung adenocarcinoma clinical specimens","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP at target promoter, histone modification analysis, KD with multiple EMT readouts, clinical specimen correlation","pmids":["28249899"],"is_preprint":false},{"year":2017,"finding":"TIEG1/KLF10 directly represses Smad7 promoter activity by binding a GC-box/Sp1 site at nucleotides -1392 to -1382, thereby promoting Smad2 phosphorylation and enhancing TGF-β/Smad signaling in keloid fibroblasts.","method":"siRNA knockdown and overexpression, luciferase reporter assay of Smad7 promoter, chromatin immunoprecipitation, collagen production and migration assays","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP at defined Smad7 promoter element, luciferase with defined binding site, bidirectional manipulation (KD and OE), multiple functional readouts","pmids":["28108300"],"is_preprint":false},{"year":2017,"finding":"TIEG1/KLF10 is involved in canonical Wnt signaling in bone: TIEG1 modulates AKT and GSK-3β activity to promote β-catenin nuclear localization, and TIEG1 physically interacts with and serves as a transcriptional co-activator for Lef1 and β-catenin.","method":"Co-immunoprecipitation (TIEG1–β-catenin, TIEG1–Lef1), subcellular fractionation, AKT/GSK-3β phosphorylation assays, KO mouse bone phenotype analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, fractionation, kinase assays, and KO mouse validation, multiple orthogonal methods","pmids":["28201653"],"is_preprint":false},{"year":2017,"finding":"KLF10 directly activates PGC-1α (Ppargc1a) gene transcription by binding to its promoter region, increasing expression of gluconeogenic genes and hepatic glucose output; hepatic KLF10 knockdown in diabetic/obese mice decreases blood glucose.","method":"Luciferase reporter gene assay, chromatin immunoprecipitation, adenoviral KLF10 overexpression/shRNA in primary hepatocytes and mouse liver, glucose tolerance and pyruvate tolerance tests","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP at Pgc-1α promoter, luciferase reporter, bidirectional in vivo manipulation in multiple diabetic mouse models","pmids":["28836014"],"is_preprint":false},{"year":2017,"finding":"Loss of KLF10 in pancreatic cancer cooperating with KrasG12D increases distant metastases and cancer stemness through activation of SDF-1/CXCR4 and AP-1 pathways; inhibition of the SDF-1/CXCR4 pathway suppresses PDAC progression in KLF10-null context.","method":"Pdx-1Cre KrasG12D KLF10 conditional KO mouse models, SDF-1/CXCR4 pathway analysis, CXCR4 inhibitor treatment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO pancreatic cancer models with pathway analysis and pharmacological rescue, single lab","pmids":["28581520"],"is_preprint":false},{"year":2018,"finding":"KDM6A (a histone lysine demethylase) upregulates KLF10 in diabetic podocytes, and KLF10 in turn represses nephrin expression by directly binding the nephrin gene promoter and recruiting DNA methyltransferase Dnmt1; KLF10 overexpression also increases KDM6A, forming a positive feedback loop.","method":"KDM6A/KLF10 overexpression/KO in podocytes, chromatin immunoprecipitation at nephrin promoter, Dnmt1 co-recruitment assay, KDM6A/KLF10 KO mouse diabetic nephropathy model","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP at target promoter, Dnmt1 recruitment, bidirectional genetic manipulation in vitro and in vivo KO models, multiple orthogonal methods","pmids":["30948420"],"is_preprint":false},{"year":2018,"finding":"C/EBPβ binds to the KLF10 promoter and transactivates KLF10 expression during mitotic clonal expansion in 3T3-L1 preadipocytes; KLF10 in turn represses C/EBPα promoter activity by recruiting HDAC1, decreasing acetylated histone H4, thereby delaying adipogenesis.","method":"Chromatin immunoprecipitation, promoter luciferase with deletion/mutation analysis, co-immunoprecipitation (KLF10–HDAC1), siRNA knockdown, histone acetylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP at multiple promoters, Co-IP of KLF10-HDAC1 complex, promoter mutation analysis, histone acetylation measurement","pmids":["30026232"],"is_preprint":false},{"year":2010,"finding":"HPV-16 E7 directly binds the C-terminus of TIEG1/KLF10 (identified by yeast two-hybrid) and promotes TIEG1 degradation via the ubiquitin pathway, attenuating TIEG1-mediated apoptosis.","method":"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, apoptosis functional assay","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid identification confirmed by Co-IP, ubiquitination assay, and functional apoptosis readout, single lab","pmids":["20691807"],"is_preprint":false},{"year":2020,"finding":"CD4+-T-cell-specific KLF10 knockout mice develop obesity, insulin resistance, and fatty liver due to defects in Treg mobilization to liver/adipose tissue and decreased TGF-β3 release; mechanistically, KLF10 KO Tregs exhibit reduced mitochondrial respiration, glycolysis, and PI3K-Akt-mTOR signaling, impairing chemotaxis. Adoptive transfer of WT Tregs fully rescues the phenotype.","method":"CD4+-T-cell-specific KLF10 KO mice, metabolic phenotyping, Treg adoptive transfer rescue, in vitro TGF-β3 ELISA, metabolic flux analysis (mitochondrial respiration and glycolysis), PI3K-Akt-mTOR signaling assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO, adoptive transfer rescue, metabolic mechanistic assays, multiple orthogonal readouts","pmids":["33378664"],"is_preprint":false},{"year":2021,"finding":"KLF10 promotes NASH progression by transcriptionally activating zDHHC7, which palmitoylates CD36 to promote its plasma membrane localization and hepatic lipid accumulation; both zDHHC7 expression and CD36 palmitoylation are required for KLF10's pathogenic role.","method":"Hepatocyte-specific KLF10 overexpression/depletion in NASH mouse models, transcriptomic analysis, luciferase reporter and ChIP for zDHHC7 promoter, CD36 palmitoylation assay, plasma membrane fractionation","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo hepatocyte-specific manipulation, ChIP at zDHHC7 promoter, palmitoylation biochemistry, and membrane fractionation across multiple models","pmids":["35492028"],"is_preprint":false},{"year":2021,"finding":"AMPK phosphorylates KLF10 at Thr189, stabilizing the protein; phosphorylated KLF10 binds the SREBP-1C promoter and represses its transcription, thereby reducing lipogenesis. Hepatic-specific KLF10 KO mice develop more severe NAFLD on a high-fat diet.","method":"In vitro and in vivo phosphorylation assays, ChIP-chip for target gene identification, SREBP-1C promoter luciferase, hepatocyte-specific KLF10 KO mouse NAFLD model, Western blotting","journal":"Frontiers in molecular biosciences","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay, ChIP-chip, promoter reporter, and in vivo KO model with metabolic phenotype","pmids":["34869587"],"is_preprint":false},{"year":2021,"finding":"KLF10 binds to the IL-9 promoter and interacts with HDAC1 to inhibit IL-9 transcription in CD4+ T cells; CD4+-T-cell-specific KLF10 deficiency leads to increased IL-9, which drives fibroblast activation, calcium mobilization, and perivascular fibrosis; anti-IL9 antibodies reverse the fibrosis.","method":"Chromatin immunoprecipitation (KLF10 at IL-9 promoter, HDAC1 interaction), TKO mouse Ang II infusion model, aortic single-cell RNA-seq, cytokine analysis, anti-IL9 therapeutic rescue","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, Co-IP with HDAC1, cell-type-specific KO, single-cell RNA-seq, and antibody rescue experiment","pmids":["35440172"],"is_preprint":false},{"year":2024,"finding":"Exercise induces KLF10 expression in liver via the cAMP/PKA/CREB pathway; KLF10 promotes fumarate hydratase 1 (Fh1) expression, thereby reducing fumarate accumulation, decreasing H3K4me3 on lipogenic gene promoters, and attenuating lipogenesis to protect against NASH.","method":"Hepatocyte-specific KLF10 KO and overexpression mouse models, treadmill exercise, cAMP/PKA/CREB pathway inhibitors, fumarate metabolomics, H3K4me3 ChIP at lipogenic gene promoters","journal":"Metabolism: clinical and experimental","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional in vivo genetic manipulation, pharmacological pathway inhibition, metabolomics, ChIP for histone marks, multiple orthogonal methods","pmids":["38615945"],"is_preprint":false},{"year":2015,"finding":"Computer-aided drug design identified small molecule inhibitors that bind a druggable pocket in the second zinc finger of KLF10, inhibiting KLF10-DNA binding and transcriptional activity, as well as conversion of CD4+CD25- T cells to CD4+CD25+ Tregs.","method":"CADD virtual screening, KLF10-DNA binding inhibition assays, T regulatory cell conversion assay, KLF10 target gene expression","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — CADD-based with functional DNA-binding and cellular T-cell assays confirming inhibition, single lab","pmids":["25581017"],"is_preprint":false},{"year":2022,"finding":"KLF10 directly binds the ACSM3 promoter and transcriptionally activates it (validated by ChIP and dual-luciferase assay); KLF10-mediated ACSM3 upregulation inhibits PI3K/Akt signaling to suppress melanoma cell proliferation, invasion, and migration.","method":"ChIP assay, dual-luciferase reporter, KLF10 overexpression and ACSM3 knockdown rescue experiments, PI3K/Akt phosphorylation assays","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and promoter reporter plus epistasis (ACSM3 KD reversing KLF10 OE effects), single lab","pmids":["35497935"],"is_preprint":false},{"year":2019,"finding":"KLF10 directly regulates the Indian hedgehog (Ihh) promoter activity in mesenchymal stem cells; KLF10 knockdown mimics miR-892b overexpression in enhancing chondrogenesis and inhibiting hypertrophy in TGF-β-mediated chondrogenesis.","method":"Luciferase assay for Ihh promoter, KLF10 knockdown in hMSC chondrogenesis, miR-892b mimic overexpression, hypertrophic and chondrogenic marker gene analysis","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Ihh promoter luciferase with KLF10 manipulation, functional MSC differentiation assay, single lab","pmids":["31284128"],"is_preprint":false},{"year":2012,"finding":"TIEG1/KLF10 missense mutations found in human HCM patients significantly increase PTTG1 promoter activity in transfection/luciferase assays compared to WT TIEG1, and PTTG1 protein is elevated in TIEG1-mutation-positive HCM cardiac tissue by immunohistochemistry.","method":"Site-directed mutagenesis, transient transfection luciferase assay for PTTG1 promoter, immunohistochemistry of cardiac tissue","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with functional promoter reporter and tissue validation, but limited to promoter activity assay for mechanism, single lab","pmids":["22234868"],"is_preprint":false},{"year":2015,"finding":"TIEG1/KLF10 inhibits Ang II-induced cardiomyocyte hypertrophy by inhibiting the expression and transcriptional activity of GATA4; TIEG1 knockdown upregulates ANF and BNP, while TIEG1 overexpression inhibits hypertrophic gene expression.","method":"siRNA knockdown and overexpression in cardiomyocytes, cellular surface area measurement, ANF/BNP mRNA quantification, GATA4 transcriptional activity assay","journal":"Journal of cardiovascular pharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — bidirectional KD/OE with multiple hypertrophy markers and GATA4 transcriptional activity, single lab","pmids":["26252173"],"is_preprint":false},{"year":2017,"finding":"TIEG1/KLF10 directly suppresses SOST (sclerostin) promoter activity; TIEG1 KO osteocytes (shRNA or CRISPR-Cas9) show increased SOST expression and delayed mineralization. Estrogen and ovariectomy modulate SOST expression in a TIEG1-dependent manner in vivo.","method":"Promoter deletion assay, chromatin immunoprecipitation, shRNA and CRISPR-Cas9 knockdown in IDG-SW3 osteocytes, OVX/ERT studies with mRNA sequencing","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, promoter deletion, two independent KD strategies in osteocytes, and in vivo ovariectomy model with transcriptomics","pmids":["29044507"],"is_preprint":false},{"year":2012,"finding":"TIEG1/KLF10 represses stathmin promoter activity in a dose-dependent manner and is required for TGF-β1-induced growth inhibition in hepatocellular carcinoma cells; siRNA knockdown of TIEG1 decreases TGF-β1 sensitivity in Hep3B cells.","method":"siRNA knockdown, TIEG1 lentiviral overexpression, luciferase assay for stathmin promoter, MTT cell viability assay, DAPI apoptosis staining","journal":"World journal of gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation with promoter reporter and multiple functional readouts, single lab","pmids":["22563190"],"is_preprint":false},{"year":2016,"finding":"KLF10 acts as a transcriptional repressor of NPRA and directly binds the NPRA promoter; KLF10-deficient mice show increased NPRA expression and exacerbated pulmonary inflammation upon LPS or ovalbumin challenge.","method":"KLF10 KO mouse pulmonary inflammation model, luciferase reporter assay showing KLF10 repression of NPRA promoter, ChIP confirming KLF10 binding to NPRA promoter, histology","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, promoter reporter, and KO mouse phenotype, single lab","pmids":["27592451"],"is_preprint":false},{"year":2022,"finding":"KLF10 directly binds the promoter of LINC00629 (confirmed by ChIP) and activates its transcription; apigenin induces KLF10 which then drives LINC00629 expression to decrease Mcl1 stability and promote apoptosis in oral squamous cell carcinoma.","method":"Chromatin immunoprecipitation of KLF10 at LINC00629 promoter, luciferase reporter assay, LINC00629-Mcl1 protein interaction and degradation assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at target promoter, promoter luciferase, downstream protein interaction characterization, single lab","pmids":["36445338"],"is_preprint":false},{"year":2020,"finding":"KLF10 deletion in liver leads to increased phosphorylation and nuclear localization of Smad3 under high-sucrose feeding, contributing to liver fibrosis; KLF10 depletion sensitizes primary hepatocytes to TNF-α-induced apoptosis via increased caspase-3 activation.","method":"Klf10 KO mouse high-sucrose diet model, Smad3 phosphorylation and nuclear localization Western blot/immunofluorescence, primary hepatocyte apoptosis with TNF-α treatment, caspase-3 assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with Smad3 pathway analysis and primary hepatocyte mechanistic follow-up, single lab","pmids":["33396939"],"is_preprint":false}],"current_model":"KLF10 (TIEG1) is a TGF-β-inducible Krüppel-like zinc finger transcription factor that binds GC-rich (Sp1/GGTGTG) promoter elements to activate or repress target genes including Smad7, EGFR, SLUG, Bmal1, PEPCK, PGC-1α, RANKL/OPG, Runx2, Osterix, FOXP3, TGF-βRII, IL-9, zDHHC7, and SOST; it represses transcription through recruitment of HDAC1, the histone demethylase JARID1B/KDM5B, and the Sin3-HDAC complex, and activates transcription by associating with PCAF and β-catenin/Lef1; its stability and nuclear localization are regulated post-translationally by RAF-1-mediated phosphorylation at Thr93 (enabling PIN1-isomerase-driven degradation), AMPK-mediated phosphorylation at Thr189 (stabilization), Tyk2-mediated phosphorylation at Tyr179 (promoting K27-polyubiquitination and cytoplasmic retention), and Itch-mediated ubiquitination (nonproteolytic, promoting Foxp3 induction); in bone KLF10 supports osteoblast mineralization and osteoclast differentiation via the RANKL/OPG axis and Wnt/β-catenin signaling, in immune cells it is essential for TGF-β-driven Treg development and suppression of inflammation, and in liver it links the circadian clock to glucose and lipid homeostasis."},"narrative":{"mechanistic_narrative":"KLF10 (TIEG1) is a TGF-β-inducible Krüppel-like zinc finger transcription factor that translates TGF-β/BMP signaling into transcriptional programs governing cell fate, immune tolerance, bone formation, and hepatic metabolism [PMID:9153278, PMID:10816551, PMID:15657444]. Its zinc finger domain binds GT/GC-rich elements (consensus 5'-GGTGTG-3' and Sp1 sites) in target promoters [PMID:12804117], and three conserved repressor domains outside the DNA-binding region mediate transcriptional repression [PMID:10506214]. KLF10 represses targets — including Smad7, EGFR, SLUG/SNAI2, and IL-9 — by occupying their promoters and recruiting HDAC1 to strip activating histone acetylation [PMID:22025675, PMID:28249899, PMID:28108300, PMID:35440172], and it engages the histone demethylase JARID1B/KDM5B and the Sin3 complex for repression while switching to activation through association with the acetyltransferase PCAF [PMID:20863814, PMID:24944246]. As an activator it directly transactivates Runx2 and Osterix to drive osteoblast differentiation [PMID:21559363, PMID:26801561] and binds the TGF-βRII promoter in T cells and macrophages to reinforce TGF-β/Smad signaling [PMID:25472963, PMID:26472224]. In immune regulation, KLF10 is essential for TGF-β-driven Treg development and suppression of inflammation, acting through a TGF-β1/Foxp3 positive-feedback loop and cooperating with the E3 ligase Itch [PMID:18278048, PMID:19602726, PMID:33378664]. In liver, KLF10 is a circadian-clock-controlled gene that represses Bmal1 and gluconeogenic/lipogenic programs, linking the clock to glucose and lipid homeostasis [PMID:20070857, PMID:20385766, PMID:28836014, PMID:34869587]. KLF10 stability and localization are set post-translationally by RAF-1/PIN1-driven degradation at Thr93, AMPK-mediated stabilization at Thr189, and Tyk2-mediated Tyr179 phosphorylation that promotes K27-ubiquitination and cytoplasmic retention [PMID:21471442, PMID:23994618, PMID:34869587]. Human KLF10 missense mutations are linked to hypertrophic cardiomyopathy through gain of PTTG1 promoter activation [PMID:22234868].","teleology":[{"year":1997,"claim":"Established KLF10 as a functional downstream effector of TGF-β rather than a passive marker, by showing its overexpression alone drives apoptosis in TGF-β-sensitive epithelial cells.","evidence":"Stable overexpression in PANC1 pancreatic cells with apoptosis readout","pmids":["9153278"],"confidence":"Medium","gaps":["Did not define direct transcriptional targets driving apoptosis","Single cell type; mechanism of cell-death induction unresolved"]},{"year":1999,"claim":"Defined the molecular grammar of KLF10 as a repressor by mapping three conserved repression domains separate from the DNA-binding region.","evidence":"Mutagenesis and GAL4 reporter assays comparing TIEG1 and TIEG2","pmids":["10506214"],"confidence":"High","gaps":["Did not identify the corepressors recruited by each domain","Domains defined in heterologous GAL4 context, not native promoters"]},{"year":1999,"claim":"Resolved the apoptotic mechanism downstream of KLF10 as mitochondrial/ROS-dependent, showing antioxidant rescue blocks death.","evidence":"ROS, mitochondrial potential, caspase, and trolox-rescue assays in Hep3B cells","pmids":["10573529"],"confidence":"High","gaps":["Did not connect ROS generation to a direct transcriptional target"]},{"year":2003,"claim":"Defined the DNA-binding specificity of KLF10, anchoring all subsequent promoter-occupancy claims to a GT-rich core motif.","evidence":"SELEX-like in vitro selection and mutational analysis of the zinc finger domain","pmids":["12804117"],"confidence":"High","gaps":["In vitro binding only; in vivo genome-wide occupancy not mapped"]},{"year":2005,"claim":"Demonstrated a physiological bone role in vivo, showing KLF10-null osteoblasts fail BMP2-induced mineralization and dysregulate the RANKL/OPG axis.","evidence":"TIEG1 KO calvarial osteoblast culture, mineralization assay, osteoclast co-culture rescue","pmids":["15657444"],"confidence":"High","gaps":["Direct promoter targets in osteoblasts not yet identified at this stage"]},{"year":2008,"claim":"Established KLF10 as essential for TGF-β-driven Treg development and immune suppression, and identified Itch as a partner mediating non-proteolytic K63 ubiquitination supporting Foxp3 induction.","evidence":"Co-IP, ubiquitination assays, Itch-/- and TIEG1-/- T cells, in vivo airway inflammation","pmids":["18278048"],"confidence":"High","gaps":["Site of K63 ubiquitination on KLF10 not mapped","How ubiquitination mechanistically enhances Foxp3 transactivation unclear"]},{"year":2008,"claim":"Defined a TGF-β1/Foxp3 positive feedback loop driven by KLF10 promoter transactivation, explaining the Treg suppressor phenotype mechanistically.","evidence":"KLF10 KO CD4+ T cell studies, promoter transactivation, Th1/Th2 profiling, atherosclerosis model","pmids":["19602726"],"confidence":"High","gaps":["Cofactors switching KLF10 to activator mode at these promoters not yet defined"]},{"year":2010,"claim":"Placed KLF10 within the circadian clock and hepatic metabolism, showing it is a CLOCK-BMAL1 target that in turn represses Bmal1 and Pepck to control glucose homeostasis.","evidence":"KLF10/Bmal1 KO mice, ChIP at Klf10 promoter, circadian bioluminescence reporters, Pepck reporter, glucose production assay","pmids":["20070857","20385766"],"confidence":"High","gaps":["Whether KLF10 repression of Bmal1 versus activation of metabolic genes uses distinct cofactors not resolved"]},{"year":2010,"claim":"Identified the chromatin-modifying machinery for KLF10 repression — the JARID1B/KDM5B demethylase binds the repression domains and augments Smad7 silencing.","evidence":"Co-IP, domain mapping, Smad7 reporter with JARID1B gain/loss","pmids":["20863814"],"confidence":"Medium","gaps":["H3K4 demethylation at the Smad7 promoter inferred from reporter data, not directly measured","Single lab"]},{"year":2011,"claim":"Established post-translational control of KLF10 function, with Tyk2-mediated Tyr179 phosphorylation triggering K27-ubiquitination and cytoplasmic retention that disables Treg development under inflammatory IL-6.","evidence":"Phosphorylation/ubiquitination assays, nuclear fractionation, Treg assays, TRAMP-C2 tumor model","pmids":["21471442"],"confidence":"High","gaps":["Identity of the K27-linkage E3 ligase not established"]},{"year":2011,"claim":"Showed KLF10 acts both as direct activator (Runx2, p21) and HDAC1-recruiting repressor (EGFR, BI-1), defining its dual transcriptional outputs in bone and cancer.","evidence":"ChIP/Co-IP at Runx2 and EGFR promoters, HDAC1 complex Co-IP, ChIP-chip/EMSA at BI-1, KO rescue and xenograft models","pmids":["21559363","22025675","21262377"],"confidence":"High","gaps":["The determinants that select activation vs repression at a given promoter not defined"]},{"year":2012,"claim":"Connected KLF10 to human disease, showing HCM-associated missense mutations aberrantly raise PTTG1 promoter activity and PTTG1 protein in patient cardiac tissue.","evidence":"Site-directed mutagenesis, PTTG1 promoter luciferase, immunohistochemistry of HCM cardiac tissue","pmids":["22234868"],"confidence":"Medium","gaps":["Causality between mutation and cardiomyopathy not demonstrated by genetic models","Single promoter assayed"]},{"year":2013,"claim":"Defined a RAF-1/PIN1 degradation axis: phosphorylation at Thr93 creates a pThr93-Pro motif recognized by PIN1 isomerase that drives KLF10 turnover.","evidence":"In vitro kinase assay, yeast two-hybrid, Thr93 mutagenesis, cycloheximide chase","pmids":["23994618"],"confidence":"High","gaps":["E3 ligase coupling PIN1 isomerization to degradation not identified"]},{"year":2014,"claim":"Revealed the molecular switch between KLF10 repression and activation at FOXP3 — an NH2-terminal Sin3-interacting domain restrains activation, and its inactivation enables PCAF recruitment.","evidence":"Domain mutagenesis, Co-IP with PCAF and Sin3-HDAC, ChIP, genome-integrated reporter, primary lymphocytes","pmids":["24944246"],"confidence":"High","gaps":["Signals that physiologically toggle the Sin3-vs-PCAF balance not identified"]},{"year":2015,"claim":"Extended the TGF-βRII activation mechanism across immune lineages, showing KLF10 promotes TGF-βRII transcription via H3 acetylation to maintain anti-inflammatory macrophage and CD8 T cell signaling.","evidence":"ChIP and H3-acetylation assays at TGF-βRII promoter, KO T cells/macrophages, cytokine profiling, adoptive transfer and viral infection models","pmids":["25472963","26472224"],"confidence":"High","gaps":["The acetyltransferase recruited at TGF-βRII not pinpointed"]},{"year":2015,"claim":"Demonstrated KLF10 is itself druggable, with CADD-identified small molecules binding the second zinc finger to block DNA binding and Treg conversion.","evidence":"Virtual screening, DNA-binding inhibition assays, Treg conversion assay","pmids":["25581017"],"confidence":"Medium","gaps":["No co-crystal structure confirming the predicted pocket","In vivo efficacy not tested"]},{"year":2017,"claim":"Established KLF10 as a tumor-suppressive brake on EMT and a regulator of Wnt and Smad7 signaling, repressing SLUG and Smad7 via HDAC1 and acting as a β-catenin/Lef1 co-activator in bone.","evidence":"ChIP/histone-acetylation at SLUG and Smad7 promoters, Co-IP with β-catenin/Lef1, AKT/GSK-3β assays, KO bone phenotype, clinical specimens","pmids":["28249899","28108300","28201653","26801561"],"confidence":"High","gaps":["Context-dependence of Smad7 repression (pro- vs anti-TGF-β outcomes) across tissues not reconciled"]},{"year":2017,"claim":"Defined KLF10 as a hepatic gluconeogenic driver by directly activating PGC-1α, providing a therapeutic target for hyperglycemia.","evidence":"ChIP and luciferase at Pgc-1α promoter, adenoviral gain/loss in hepatocytes and liver, glucose/pyruvate tolerance tests in diabetic mice","pmids":["28836014"],"confidence":"High","gaps":["Integration with circadian Pepck regulation not directly addressed"]},{"year":2021,"claim":"Resolved KLF10's role in fatty liver disease, showing it activates SREBP-1C-repressive and zDHHC7/CD36-palmitoylation pathways under AMPK control, with opposing lipogenic and protective outcomes.","evidence":"AMPK phosphorylation of Thr189, ChIP at SREBP-1C and zDHHC7 promoters, CD36 palmitoylation/membrane fractionation, hepatocyte-specific KO NAFLD/NASH models","pmids":["34869587","35492028"],"confidence":"High","gaps":["Reconciling KLF10 as both lipogenesis-suppressing (SREBP-1C) and NASH-promoting (zDHHC7/CD36) within one tissue not fully integrated"]},{"year":2022,"claim":"Linked KLF10 in T cells to organ fibrosis, showing it represses IL-9 via HDAC1 and that its loss drives perivascular fibrosis reversible by anti-IL9 antibody.","evidence":"ChIP at IL-9 promoter, HDAC1 Co-IP, CD4-specific KO Ang II model, aortic scRNA-seq, antibody rescue","pmids":["35440172"],"confidence":"High","gaps":["Whether IL-9 repression depends on the same TGF-β feedback loop as Foxp3 not established"]},{"year":2024,"claim":"Identified an exercise-responsive cAMP/PKA/CREB → KLF10 → fumarate hydratase axis that lowers fumarate and H3K4me3 on lipogenic genes to protect against NASH.","evidence":"Hepatocyte-specific KO/overexpression mice, treadmill exercise, pathway inhibitors, fumarate metabolomics, H3K4me3 ChIP","pmids":["38615945"],"confidence":"High","gaps":["Whether Fh1 is a direct KLF10 transcriptional target versus indirect not fully resolved"]},{"year":null,"claim":"How KLF10 selects activation versus repression at a given target, and which cofactor/phosphorylation state dictates the choice in each tissue, remains the central unresolved question.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of KLF10 bound to coactivator vs corepressor complexes","No genome-wide occupancy map distinguishing activated vs repressed loci","Logic integrating Thr93/Thr189/Tyr179 phosphomarks with transcriptional output undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,4,11,14,17,18,27,28,29,31]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,22,19]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[16,30]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,11,23,29]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,11,16,25,39]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,4,18,28,31]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[14,31,37,38,40]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[13,14]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[15,18,24,28,34]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,6,9,19]}],"complexes":[],"partners":["HDAC1","PCAF","JARID1B","ITCH","PIN1","CTNNB1","LEF1","RUNX2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13118","full_name":"Krueppel-like factor 10","aliases":["EGR-alpha","Transforming growth factor-beta-inducible early growth response protein 1","TGFB-inducible early growth response protein 1","TIEG-1"],"length_aa":480,"mass_kda":52.6,"function":"Transcriptional repressor which binds to the consensus sequence 5'-GGTGTG-3'. Plays a role in the regulation of the circadian clock; binds to the GC box sequence in the promoter of the core clock component ARTNL/BMAL1 and represses its transcriptional activity. Regulates the circadian expression of genes involved in lipogenesis, gluconeogenesis, and glycolysis in the liver. Represses the expression of PCK2, a rate-limiting step enzyme of gluconeogenesis (By similarity). May play a role in the cell cycle regulation","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13118/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KLF10","classification":"Not Classified","n_dependent_lines":60,"n_total_lines":1208,"dependency_fraction":0.04966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KLF10","total_profiled":1310},"omim":[{"mim_id":"603301","title":"KLF TRANSCRIPTION FACTOR 11; KLF11","url":"https://www.omim.org/entry/603301"},{"mim_id":"601878","title":"KLF TRANSCRIPTION FACTOR 10; KLF10","url":"https://www.omim.org/entry/601878"},{"mim_id":"601692","title":"TRANSFORMING GROWTH FACTOR, BETA-INDUCED, 68-KD; TGFBI","url":"https://www.omim.org/entry/601692"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KLF10"},"hgnc":{"alias_symbol":["EGRA","TIEG1"],"prev_symbol":["TIEG"]},"alphafold":{"accession":"Q13118","domains":[{"cath_id":"3.30.160","chopping":"428-457","consensus_level":"medium","plddt":79.5073,"start":428,"end":457}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13118","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13118-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13118-F1-predicted_aligned_error_v6.png","plddt_mean":49.84},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KLF10","jax_strain_url":"https://www.jax.org/strain/search?query=KLF10"},"sequence":{"accession":"Q13118","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13118.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13118/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13118"}},"corpus_meta":[{"pmid":"9153278","id":"PMC_9153278","title":"Overexpression of the TGFbeta-regulated zinc finger encoding gene, TIEG, induces apoptosis in pancreatic epithelial cells.","date":"1997","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/9153278","citation_count":200,"is_preprint":false},{"pmid":"18278048","id":"PMC_18278048","title":"The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1.","date":"2008","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18278048","citation_count":148,"is_preprint":false},{"pmid":"10573529","id":"PMC_10573529","title":"The transforming growth factor beta(1)-inducible transcription factor TIEG1, mediates apoptosis through oxidative stress.","date":"1999","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/10573529","citation_count":142,"is_preprint":false},{"pmid":"28796257","id":"PMC_28796257","title":"LncRNA OIP5-AS1 loss-induced microRNA-410 accumulation regulates cell proliferation and apoptosis by targeting KLF10 via activating PTEN/PI3K/AKT pathway in multiple myeloma.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28796257","citation_count":135,"is_preprint":false},{"pmid":"10506214","id":"PMC_10506214","title":"Three conserved transcriptional repressor domains are a defining feature of the TIEG subfamily of Sp1-like zinc finger proteins.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10506214","citation_count":105,"is_preprint":false},{"pmid":"20087894","id":"PMC_20087894","title":"Functional role of KLF10 in multiple disease processes.","date":"2010","source":"BioFactors (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/20087894","citation_count":100,"is_preprint":false},{"pmid":"15657444","id":"PMC_15657444","title":"TIEG1 null mouse-derived osteoblasts are defective in mineralization and in support of 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hematology/oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28085748","citation_count":11,"is_preprint":false},{"pmid":"38217021","id":"PMC_38217021","title":"Klf10 is involved in extracellular matrix calcification of chondrocytes alleviating chondrocyte senescence.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38217021","citation_count":11,"is_preprint":false},{"pmid":"12065093","id":"PMC_12065093","title":"Absence of mutations in the transforming growth factor-beta inducible early gene 1, TIEG1, in pancreatic cancer.","date":"2002","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/12065093","citation_count":11,"is_preprint":false},{"pmid":"29044507","id":"PMC_29044507","title":"TIEG and estrogen modulate SOST expression in the murine skeleton.","date":"2017","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29044507","citation_count":10,"is_preprint":false},{"pmid":"26252173","id":"PMC_26252173","title":"TIEG1 Inhibits Angiotensin II-induced Cardiomyocyte Hypertrophy by Inhibiting Transcription Factor GATA4.","date":"2015","source":"Journal of cardiovascular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26252173","citation_count":10,"is_preprint":false},{"pmid":"20691807","id":"PMC_20691807","title":"The human papillomavirus-16 (HPV-16) oncoprotein E7 conjugates with and mediates the role of the transforming growth factor-beta inducible early gene 1 (TIEG1) in apoptosis.","date":"2010","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20691807","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51322,"output_tokens":12708,"usd":0.172293,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":24126,"output_tokens":6183,"usd":0.137602,"stage2_stop_reason":"end_turn"},"total_usd":0.309895,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Overexpression of TIEG1/KLF10 in TGF-β-sensitive PANC1 pancreatic epithelial cells is sufficient to induce apoptosis, establishing KLF10 as a downstream effector linking TGF-β signaling to cell death.\",\n      \"method\": \"Stable overexpression in PANC1 cells with functional apoptosis readout\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean overexpression with defined apoptotic phenotype, single lab but clearly described functional consequence\",\n      \"pmids\": [\"9153278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TIEG1/KLF10 contains three conserved transcriptional repressor domains (R1: 10 aa, R2: 12 aa, R3: ~80 aa) outside the zinc finger DNA-binding domain that are functionally conserved between TIEG1 and TIEG2, as defined by extensive mutagenesis and GAL4-based transcriptional assays.\",\n      \"method\": \"Extensive mutagenesis combined with GAL4-based transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis with functional reporter assays, multiple domains defined with orthogonal validation\",\n      \"pmids\": [\"10506214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TIEG1/KLF10-induced apoptosis in Hep 3B cells proceeds via a mechanism involving increased reactive oxygen species generation and loss of mitochondrial membrane potential, preceding caspase-3 activation and glutathione depletion; the antioxidant trolox blocks both ROS and apoptosis.\",\n      \"method\": \"ROS measurement, mitochondrial membrane potential assay, caspase activity assay, antioxidant rescue experiment in Hep 3B cells\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal mechanistic assays (ROS, mitochondrial potential, caspase, antioxidant rescue) in a single rigorous study establishing the apoptotic sequence\",\n      \"pmids\": [\"10573529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Stable overexpression of TIEG1/KLF10 in human osteosarcoma MG-63 cells mimics TGF-β action: increased alkaline phosphatase activity, decreased osteocalcin mRNA/protein, and decreased cell proliferation, without additive effect upon TGF-β treatment.\",\n      \"method\": \"Stable transfection of TIEG cDNA in MG-63 cells with gene expression and proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean overexpression model with multiple functional readouts, single lab\",\n      \"pmids\": [\"10816551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The zinc finger domain of TIEG1/KLF10 binds a GT-rich consensus core sequence (5'-GGTGTG-3') as established by iterative nitrocellulose filter-binding selection from a random oligonucleotide library and mutational analysis.\",\n      \"method\": \"In vitro selection from random oligonucleotide library (SELEX-like), nitrocellulose filter binding, mutational analysis of binding site\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical binding assay with mutagenesis identifying necessary core sequence, single lab\",\n      \"pmids\": [\"12804117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Nitric oxide (NO) upregulates TIEG1/KLF10 mRNA in human IMR-90 fibroblasts by stabilizing the transcript (6-fold increase in half-life), independently of TGF-β, as shown by anti-TGF-β antibody blocking and mRNA half-life measurements.\",\n      \"method\": \"Northern blotting, anti-TGF-β antibody neutralization, mRNA stability assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal approaches (neutralization and half-life measurement), single lab\",\n      \"pmids\": [\"12788480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TIEG1/KLF10 overexpression in oligodendroglial OLI-neu cells induces apoptosis by repressing Bcl-XL expression and enhancing SMAD-dependent TGF-β signaling, while reducing SMAD7 promoter activity.\",\n      \"method\": \"Overexpression in OLI-neu cells, apoptosis ELISA, DNA fragmentation, caspase-3 assay, luciferase reporter for SMAD7 promoter\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal apoptosis assays plus promoter reporter, single lab\",\n      \"pmids\": [\"14743447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TIEG1/KLF10 knockout osteoblasts are defective in BMP2-induced mineralization in vitro and show decreased RANKL and increased OPG expression, resulting in impaired support of osteoclast differentiation.\",\n      \"method\": \"TIEG1 knockout mouse calvarial osteoblast culture, BMP2 treatment, mineralization nodule assay, osteoclast co-culture with RANKL/M-CSF rescue\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with multiple cellular phenotypes and partial rescue experiments, replicated across multiple assays in one rigorous study\",\n      \"pmids\": [\"15657444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"BMP2 opposes Shh-mediated proliferation in cerebellar granule neuron precursors by inducing TIEG1/KLF10, which occupies Sp1 sites in the N-myc promoter and blocks N-myc expression, leading to cell cycle arrest.\",\n      \"method\": \"Chromatin occupancy at Nmyc promoter, ectopic TIEG1 expression in cerebellar granule neuron precursors, cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter occupancy plus functional overexpression in primary cells, single lab\",\n      \"pmids\": [\"17951258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TIEG1/KLF10 induces apoptosis through the mitochondrial pathway in K562 leukemia cells, involving Bax and Bim up-regulation, Bcl-2 and Bcl-XL down-regulation, cytochrome c release, caspase-3 activation, and mitochondrial membrane potential disruption.\",\n      \"method\": \"TIEG1 overexpression in K562 cells, Western blotting for Bcl-2 family members, cytochrome c release assay, caspase-3 activity, mitochondrial membrane potential measurement\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic markers of mitochondrial apoptosis measured in parallel, single lab\",\n      \"pmids\": [\"17659279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The E3 ubiquitin ligase Itch associates with TIEG1/KLF10 and promotes its non-proteolytic K63-linked ubiquitination; this cooperates with TIEG1 to induce Foxp3 expression in T cells, and TGF-β-converted Tregs from TIEG1-deficient mice fail to suppress airway inflammation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Itch-/- and TIEG1-/- mouse T cell functional studies, in vivo airway inflammation model\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ubiquitination assay, multiple KO mouse models, in vivo functional rescue, published in high-tier journal\",\n      \"pmids\": [\"18278048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KLF10 directly transactivates both the TGF-β1 and Foxp3 promoters in CD4+ T cells in response to TGF-β1, forming a positive feedback loop; KLF10-/- CD4+CD25- T cells show enhanced Th1/Th2 differentiation and cannot be suppressed by wild-type Tregs, while KLF10-/- Tregs have reduced TGF-β1 production and suppressor function rescued by exogenous TGF-β1.\",\n      \"method\": \"KLF10 KO mouse CD4+ T cell functional studies, promoter transactivation assays, Th1/Th2 cytokine profiling, atherosclerosis model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO model, promoter transactivation, multiple functional readouts and in vivo atherosclerosis model, comprehensive mechanistic characterization\",\n      \"pmids\": [\"19602726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KLF10 is a VHL target gene; KLF10 transactivates the TGFBI (BIGH3) promoter as assessed by luciferase reporter assay, establishing KLF10 as an intermediate between VHL status and ECM gene expression in clear cell carcinoma.\",\n      \"method\": \"Expression arrays, luciferase reporter assay of TGFBI promoter with KLF10 co-transfection, cell lines with different VHL status\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase reporter with co-transfection; VHL control established via expression arrays, single lab\",\n      \"pmids\": [\"18359287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TIEG1/KLF10 directly binds the Bmal1 promoter through two juxtaposed GC boxes near the transcription initiation site and represses Bmal1 transcription; siRNA knockdown of TIEG1 causes period shortening in cellular bioluminescence rhythms driven by Bmal1-luciferase and Per2-luciferase reporters.\",\n      \"method\": \"In vitro transcription assay, luciferase reporter with mutational analysis, siRNA knockdown, real-time bioluminescence circadian assay\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding demonstrated, promoter mutational analysis, live-cell circadian reporter rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"20070857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KLF10 displays circadian expression in mouse liver driven by CLOCK-BMAL1; the Klf10 promoter recruits BMAL1 and is transactivated by CLOCK-BMAL1 through a conserved E-box. KLF10 deficiency in liver causes postprandial/fasting hyperglycemia with upregulation of Pepck; KLF10 directly represses the Pepck promoter.\",\n      \"method\": \"KLF10 KO mice, Bmal1 KO mice, chromatin immunoprecipitation of BMAL1 at Klf10 promoter, liver transcriptome profiling, luciferase reporter for Pepck promoter, hepatic glucose production assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO models, ChIP, promoter luciferase, transcriptomics, and metabolic phenotyping, multiple orthogonal methods\",\n      \"pmids\": [\"20385766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"JARID1B/KDM5B is a corepressor of TIEG1/KLF10: the repression domains of TIEG1 bind the C-terminus of JARID1B. JARID1B overexpression augments TIEG1-mediated repression of Smad7; JARID1B knockdown increases Smad7 mRNA, indicating TIEG1 represses transcription through histone H3K4 demethylation.\",\n      \"method\": \"Co-immunoprecipitation (TIEG1–JARID1B), domain mapping, Smad7 reporter assay with JARID1B overexpression/knockdown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping and functional reporter, single lab\",\n      \"pmids\": [\"20863814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-6 activates Tyk2, which phosphorylates TIEG1/KLF10 at Tyr179, promoting non-canonical K27-linked polyubiquitination that inhibits TIEG1 nuclear translocation and thereby abrogates TGF-β-induced Treg development.\",\n      \"method\": \"Phosphorylation assays, ubiquitination assays, nuclear fractionation, functional Treg development assay, TRAMP-C2 tumor model in TIEG1-/- mice\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple biochemical assays (phosphorylation, ubiquitination, fractionation) plus in vivo tumor model, comprehensive mechanistic pathway\",\n      \"pmids\": [\"21471442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TIEG1/KLF10 directly binds to and activates the Runx2 promoter (via its zinc finger domain) and physically associates with Runx2 protein to co-activate Runx2 transcriptional activity; TGF-β1 and BMP2 induction of Runx2 requires TIEG1 expression.\",\n      \"method\": \"Transient transfection with promoter deletion constructs, chromatin immunoprecipitation, co-immunoprecipitation, adenoviral Runx2 rescue in KO osteoblasts\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, Co-IP, promoter deletion mutant analysis, and KO rescue experiments in primary cells\",\n      \"pmids\": [\"21559363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TIEG1/KLF10 suppresses breast cancer cell invasion and mammary tumorigenesis by directly binding to the EGFR promoter at Sp1 sites, recruiting HDAC1, suppressing histone acetylation, and thereby inhibiting EGFR transcription.\",\n      \"method\": \"TIEG1 overexpression/knockdown, chromatin immunoprecipitation, co-immunoprecipitation of TIEG1-HDAC1 complex, EGFR promoter binding, invasion assay, xenograft model\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP for complex, ChIP at EGFR promoter, overexpression/knockdown with invasion and in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"22025675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Klf10 directly modulates transcription of BI-1 (Bax inhibitor-1) by binding to the BI-1 promoter, as confirmed by ChIP-chip, EMSA, and BI-1 promoter mutation that abolishes Klf10-mediated repression; reduced BI-1 increases cytosolic Ca2+ and induces apoptosis in estrogen-responding breast cancer cells.\",\n      \"method\": \"ChIP-chip, EMSA, BI-1 promoter luciferase with binding site mutation, si-KLF10 rescue, intracellular Ca2+ measurement\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP-chip plus EMSA plus promoter mutation plus Ca2+ functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"21262377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KLF10 dose-dependently activates p21WAF1/CIP1 transcription independently of p53 and Sp1 binding sites, and KLF10-deficient mice exhibit increased susceptibility to skin tumorigenesis after DMBA/TPA treatment.\",\n      \"method\": \"KLF10 KO mouse tumorigenesis model, p21 promoter luciferase assay with deletion/mutation, colony formation assay after H-Ras transfection\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO in vivo model plus promoter reporter, but single lab\",\n      \"pmids\": [\"22349513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KLF10 stability is regulated by RAF-1-mediated phosphorylation at Thr93 and subsequent interaction with the prolyl isomerase PIN1 (identified by yeast two-hybrid); PIN1 binding (phosphorylation-dependent, via the pThr93-Pro motif) promotes KLF10 protein degradation.\",\n      \"method\": \"In vitro and in vivo phosphorylation assays, yeast two-hybrid screening, site-directed mutagenesis of Thr93, protein-protein interaction assays, cycloheximide chase, in vitro kinase assay with RAF-1\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay, yeast two-hybrid, mutagenesis, and cycloheximide chase providing multiple lines of evidence for the mechanism\",\n      \"pmids\": [\"23994618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KLF10 represses FGFR1 promoter activity in myoblasts by binding to the proximal Sp1 binding site of the FGFR1 promoter, competing with Sp1, thereby reducing myoblast proliferation by 86%.\",\n      \"method\": \"Southwestern blot, electromobility shift assay (EMSA), chromatin immunoprecipitation, FGFR1 promoter luciferase in myoblasts and Drosophila SL2 cells, cell proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct DNA binding shown by EMSA and ChIP, functional promoter assay, proliferation phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"23569208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KLF10 directly binds to the TGF-βRII promoter in CD8+ T cells, activating its transcription; KLF10-deficient CD8+ T cells show reduced TGF-βRII surface expression and attenuated Smad2 phosphorylation after TGF-β1 stimulation.\",\n      \"method\": \"Chromatin immunoprecipitation, TGF-βRII promoter binding assay, KLF10-/- mouse CD8+ T cell phenotyping, flow cytometry for TGF-βRII, phospho-Smad2 measurement, in vivo viral infection model\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP at TGF-βRII promoter plus KO mouse functional studies plus in vivo viral model, replicated in multiple contexts\",\n      \"pmids\": [\"25472963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KLF10 integrates antagonistic epigenetic signals at the FOXP3 promoter: an NH2-terminal Sin3-interacting repressor domain limits KLF10 activation, while inactivation of this domain enables KLF10 to physically associate with the histone acetyltransferase PCAF to induce FOXP3 gene transcription.\",\n      \"method\": \"Chromatin immunoprecipitation, genome-integrated reporter assay, functional domain KLF10 mutant proteins, Co-IP with PCAF and Sin3-HDAC complex, primary murine lymphocyte validation\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mutagenesis, Co-IP with two opposing complexes, ChIP, genome-integrated reporter, and primary cell validation\",\n      \"pmids\": [\"24944246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KLF10 directly binds to the TGF-βRII promoter in macrophages, enhancing its transcription through histone H3 acetylation; KLF10-deficient macrophages show reduced TGF-βRII expression, attenuated Smad2 phosphorylation, and a pro-inflammatory cytokine profile (increased TNF-α, decreased IL-10).\",\n      \"method\": \"Chromatin immunoprecipitation, KLF10-/- mouse bone marrow-derived macrophage studies, H3 acetylation assay at TGF-βRII promoter, cytokine ELISA, adoptive transfer of KO macrophages\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP with histone mark, KO macrophages, cytokine profiling, and adoptive transfer model\",\n      \"pmids\": [\"26472224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KLF10 transcriptionally activates the SEI-1 promoter and induces SEI-1 protein expression in pancreatic carcinoma cells, subsequently increasing p21Cip1 expression; KLF10-deficient mice show decreased pancreatic islet mass with nuclear accumulation of p21Cip1.\",\n      \"method\": \"ChIP-chip identification of SEI-1 as KLF10 target, luciferase promoter assay, KLF10 KO mouse islet histology\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-chip, promoter reporter, and KO mouse phenotype, but limited functional rescue data, single lab\",\n      \"pmids\": [\"25578559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TIEG1/KLF10 directly binds to and activates the Osterix promoter (via its zinc finger DNA-binding domain) in osteoblasts; TIEG1 is required for induction of Osterix by TGF-β1 and BMP2.\",\n      \"method\": \"Transient transfection with Osterix promoter constructs, chromatin immunoprecipitation, shRNA and CRISPR knockdown of TIEG1, KO osteoblast complementation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, promoter deletion analysis, multiple KD strategies and KO rescue in primary osteoblasts\",\n      \"pmids\": [\"26801561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KLF10 suppresses TGF-β-induced EMT by occupying GC-rich sequences in the SLUG/SNAI2 promoter, recruiting HDAC1, and removing activating histone acetylation marks to repress SLUG transcription.\",\n      \"method\": \"KLF10 depletion (siRNA/shRNA), chromatin immunoprecipitation at SLUG promoter, histone acetylation assay, EMT marker panel, lung adenocarcinoma clinical specimens\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP at target promoter, histone modification analysis, KD with multiple EMT readouts, clinical specimen correlation\",\n      \"pmids\": [\"28249899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TIEG1/KLF10 directly represses Smad7 promoter activity by binding a GC-box/Sp1 site at nucleotides -1392 to -1382, thereby promoting Smad2 phosphorylation and enhancing TGF-β/Smad signaling in keloid fibroblasts.\",\n      \"method\": \"siRNA knockdown and overexpression, luciferase reporter assay of Smad7 promoter, chromatin immunoprecipitation, collagen production and migration assays\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP at defined Smad7 promoter element, luciferase with defined binding site, bidirectional manipulation (KD and OE), multiple functional readouts\",\n      \"pmids\": [\"28108300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TIEG1/KLF10 is involved in canonical Wnt signaling in bone: TIEG1 modulates AKT and GSK-3β activity to promote β-catenin nuclear localization, and TIEG1 physically interacts with and serves as a transcriptional co-activator for Lef1 and β-catenin.\",\n      \"method\": \"Co-immunoprecipitation (TIEG1–β-catenin, TIEG1–Lef1), subcellular fractionation, AKT/GSK-3β phosphorylation assays, KO mouse bone phenotype analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, fractionation, kinase assays, and KO mouse validation, multiple orthogonal methods\",\n      \"pmids\": [\"28201653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KLF10 directly activates PGC-1α (Ppargc1a) gene transcription by binding to its promoter region, increasing expression of gluconeogenic genes and hepatic glucose output; hepatic KLF10 knockdown in diabetic/obese mice decreases blood glucose.\",\n      \"method\": \"Luciferase reporter gene assay, chromatin immunoprecipitation, adenoviral KLF10 overexpression/shRNA in primary hepatocytes and mouse liver, glucose tolerance and pyruvate tolerance tests\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP at Pgc-1α promoter, luciferase reporter, bidirectional in vivo manipulation in multiple diabetic mouse models\",\n      \"pmids\": [\"28836014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of KLF10 in pancreatic cancer cooperating with KrasG12D increases distant metastases and cancer stemness through activation of SDF-1/CXCR4 and AP-1 pathways; inhibition of the SDF-1/CXCR4 pathway suppresses PDAC progression in KLF10-null context.\",\n      \"method\": \"Pdx-1Cre KrasG12D KLF10 conditional KO mouse models, SDF-1/CXCR4 pathway analysis, CXCR4 inhibitor treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO pancreatic cancer models with pathway analysis and pharmacological rescue, single lab\",\n      \"pmids\": [\"28581520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM6A (a histone lysine demethylase) upregulates KLF10 in diabetic podocytes, and KLF10 in turn represses nephrin expression by directly binding the nephrin gene promoter and recruiting DNA methyltransferase Dnmt1; KLF10 overexpression also increases KDM6A, forming a positive feedback loop.\",\n      \"method\": \"KDM6A/KLF10 overexpression/KO in podocytes, chromatin immunoprecipitation at nephrin promoter, Dnmt1 co-recruitment assay, KDM6A/KLF10 KO mouse diabetic nephropathy model\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP at target promoter, Dnmt1 recruitment, bidirectional genetic manipulation in vitro and in vivo KO models, multiple orthogonal methods\",\n      \"pmids\": [\"30948420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"C/EBPβ binds to the KLF10 promoter and transactivates KLF10 expression during mitotic clonal expansion in 3T3-L1 preadipocytes; KLF10 in turn represses C/EBPα promoter activity by recruiting HDAC1, decreasing acetylated histone H4, thereby delaying adipogenesis.\",\n      \"method\": \"Chromatin immunoprecipitation, promoter luciferase with deletion/mutation analysis, co-immunoprecipitation (KLF10–HDAC1), siRNA knockdown, histone acetylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP at multiple promoters, Co-IP of KLF10-HDAC1 complex, promoter mutation analysis, histone acetylation measurement\",\n      \"pmids\": [\"30026232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HPV-16 E7 directly binds the C-terminus of TIEG1/KLF10 (identified by yeast two-hybrid) and promotes TIEG1 degradation via the ubiquitin pathway, attenuating TIEG1-mediated apoptosis.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, apoptosis functional assay\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid identification confirmed by Co-IP, ubiquitination assay, and functional apoptosis readout, single lab\",\n      \"pmids\": [\"20691807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD4+-T-cell-specific KLF10 knockout mice develop obesity, insulin resistance, and fatty liver due to defects in Treg mobilization to liver/adipose tissue and decreased TGF-β3 release; mechanistically, KLF10 KO Tregs exhibit reduced mitochondrial respiration, glycolysis, and PI3K-Akt-mTOR signaling, impairing chemotaxis. Adoptive transfer of WT Tregs fully rescues the phenotype.\",\n      \"method\": \"CD4+-T-cell-specific KLF10 KO mice, metabolic phenotyping, Treg adoptive transfer rescue, in vitro TGF-β3 ELISA, metabolic flux analysis (mitochondrial respiration and glycolysis), PI3K-Akt-mTOR signaling assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO, adoptive transfer rescue, metabolic mechanistic assays, multiple orthogonal readouts\",\n      \"pmids\": [\"33378664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KLF10 promotes NASH progression by transcriptionally activating zDHHC7, which palmitoylates CD36 to promote its plasma membrane localization and hepatic lipid accumulation; both zDHHC7 expression and CD36 palmitoylation are required for KLF10's pathogenic role.\",\n      \"method\": \"Hepatocyte-specific KLF10 overexpression/depletion in NASH mouse models, transcriptomic analysis, luciferase reporter and ChIP for zDHHC7 promoter, CD36 palmitoylation assay, plasma membrane fractionation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo hepatocyte-specific manipulation, ChIP at zDHHC7 promoter, palmitoylation biochemistry, and membrane fractionation across multiple models\",\n      \"pmids\": [\"35492028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AMPK phosphorylates KLF10 at Thr189, stabilizing the protein; phosphorylated KLF10 binds the SREBP-1C promoter and represses its transcription, thereby reducing lipogenesis. Hepatic-specific KLF10 KO mice develop more severe NAFLD on a high-fat diet.\",\n      \"method\": \"In vitro and in vivo phosphorylation assays, ChIP-chip for target gene identification, SREBP-1C promoter luciferase, hepatocyte-specific KLF10 KO mouse NAFLD model, Western blotting\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay, ChIP-chip, promoter reporter, and in vivo KO model with metabolic phenotype\",\n      \"pmids\": [\"34869587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KLF10 binds to the IL-9 promoter and interacts with HDAC1 to inhibit IL-9 transcription in CD4+ T cells; CD4+-T-cell-specific KLF10 deficiency leads to increased IL-9, which drives fibroblast activation, calcium mobilization, and perivascular fibrosis; anti-IL9 antibodies reverse the fibrosis.\",\n      \"method\": \"Chromatin immunoprecipitation (KLF10 at IL-9 promoter, HDAC1 interaction), TKO mouse Ang II infusion model, aortic single-cell RNA-seq, cytokine analysis, anti-IL9 therapeutic rescue\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, Co-IP with HDAC1, cell-type-specific KO, single-cell RNA-seq, and antibody rescue experiment\",\n      \"pmids\": [\"35440172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Exercise induces KLF10 expression in liver via the cAMP/PKA/CREB pathway; KLF10 promotes fumarate hydratase 1 (Fh1) expression, thereby reducing fumarate accumulation, decreasing H3K4me3 on lipogenic gene promoters, and attenuating lipogenesis to protect against NASH.\",\n      \"method\": \"Hepatocyte-specific KLF10 KO and overexpression mouse models, treadmill exercise, cAMP/PKA/CREB pathway inhibitors, fumarate metabolomics, H3K4me3 ChIP at lipogenic gene promoters\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional in vivo genetic manipulation, pharmacological pathway inhibition, metabolomics, ChIP for histone marks, multiple orthogonal methods\",\n      \"pmids\": [\"38615945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Computer-aided drug design identified small molecule inhibitors that bind a druggable pocket in the second zinc finger of KLF10, inhibiting KLF10-DNA binding and transcriptional activity, as well as conversion of CD4+CD25- T cells to CD4+CD25+ Tregs.\",\n      \"method\": \"CADD virtual screening, KLF10-DNA binding inhibition assays, T regulatory cell conversion assay, KLF10 target gene expression\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — CADD-based with functional DNA-binding and cellular T-cell assays confirming inhibition, single lab\",\n      \"pmids\": [\"25581017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KLF10 directly binds the ACSM3 promoter and transcriptionally activates it (validated by ChIP and dual-luciferase assay); KLF10-mediated ACSM3 upregulation inhibits PI3K/Akt signaling to suppress melanoma cell proliferation, invasion, and migration.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter, KLF10 overexpression and ACSM3 knockdown rescue experiments, PI3K/Akt phosphorylation assays\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and promoter reporter plus epistasis (ACSM3 KD reversing KLF10 OE effects), single lab\",\n      \"pmids\": [\"35497935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KLF10 directly regulates the Indian hedgehog (Ihh) promoter activity in mesenchymal stem cells; KLF10 knockdown mimics miR-892b overexpression in enhancing chondrogenesis and inhibiting hypertrophy in TGF-β-mediated chondrogenesis.\",\n      \"method\": \"Luciferase assay for Ihh promoter, KLF10 knockdown in hMSC chondrogenesis, miR-892b mimic overexpression, hypertrophic and chondrogenic marker gene analysis\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Ihh promoter luciferase with KLF10 manipulation, functional MSC differentiation assay, single lab\",\n      \"pmids\": [\"31284128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TIEG1/KLF10 missense mutations found in human HCM patients significantly increase PTTG1 promoter activity in transfection/luciferase assays compared to WT TIEG1, and PTTG1 protein is elevated in TIEG1-mutation-positive HCM cardiac tissue by immunohistochemistry.\",\n      \"method\": \"Site-directed mutagenesis, transient transfection luciferase assay for PTTG1 promoter, immunohistochemistry of cardiac tissue\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with functional promoter reporter and tissue validation, but limited to promoter activity assay for mechanism, single lab\",\n      \"pmids\": [\"22234868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TIEG1/KLF10 inhibits Ang II-induced cardiomyocyte hypertrophy by inhibiting the expression and transcriptional activity of GATA4; TIEG1 knockdown upregulates ANF and BNP, while TIEG1 overexpression inhibits hypertrophic gene expression.\",\n      \"method\": \"siRNA knockdown and overexpression in cardiomyocytes, cellular surface area measurement, ANF/BNP mRNA quantification, GATA4 transcriptional activity assay\",\n      \"journal\": \"Journal of cardiovascular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — bidirectional KD/OE with multiple hypertrophy markers and GATA4 transcriptional activity, single lab\",\n      \"pmids\": [\"26252173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TIEG1/KLF10 directly suppresses SOST (sclerostin) promoter activity; TIEG1 KO osteocytes (shRNA or CRISPR-Cas9) show increased SOST expression and delayed mineralization. Estrogen and ovariectomy modulate SOST expression in a TIEG1-dependent manner in vivo.\",\n      \"method\": \"Promoter deletion assay, chromatin immunoprecipitation, shRNA and CRISPR-Cas9 knockdown in IDG-SW3 osteocytes, OVX/ERT studies with mRNA sequencing\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, promoter deletion, two independent KD strategies in osteocytes, and in vivo ovariectomy model with transcriptomics\",\n      \"pmids\": [\"29044507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TIEG1/KLF10 represses stathmin promoter activity in a dose-dependent manner and is required for TGF-β1-induced growth inhibition in hepatocellular carcinoma cells; siRNA knockdown of TIEG1 decreases TGF-β1 sensitivity in Hep3B cells.\",\n      \"method\": \"siRNA knockdown, TIEG1 lentiviral overexpression, luciferase assay for stathmin promoter, MTT cell viability assay, DAPI apoptosis staining\",\n      \"journal\": \"World journal of gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation with promoter reporter and multiple functional readouts, single lab\",\n      \"pmids\": [\"22563190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KLF10 acts as a transcriptional repressor of NPRA and directly binds the NPRA promoter; KLF10-deficient mice show increased NPRA expression and exacerbated pulmonary inflammation upon LPS or ovalbumin challenge.\",\n      \"method\": \"KLF10 KO mouse pulmonary inflammation model, luciferase reporter assay showing KLF10 repression of NPRA promoter, ChIP confirming KLF10 binding to NPRA promoter, histology\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, promoter reporter, and KO mouse phenotype, single lab\",\n      \"pmids\": [\"27592451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KLF10 directly binds the promoter of LINC00629 (confirmed by ChIP) and activates its transcription; apigenin induces KLF10 which then drives LINC00629 expression to decrease Mcl1 stability and promote apoptosis in oral squamous cell carcinoma.\",\n      \"method\": \"Chromatin immunoprecipitation of KLF10 at LINC00629 promoter, luciferase reporter assay, LINC00629-Mcl1 protein interaction and degradation assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at target promoter, promoter luciferase, downstream protein interaction characterization, single lab\",\n      \"pmids\": [\"36445338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KLF10 deletion in liver leads to increased phosphorylation and nuclear localization of Smad3 under high-sucrose feeding, contributing to liver fibrosis; KLF10 depletion sensitizes primary hepatocytes to TNF-α-induced apoptosis via increased caspase-3 activation.\",\n      \"method\": \"Klf10 KO mouse high-sucrose diet model, Smad3 phosphorylation and nuclear localization Western blot/immunofluorescence, primary hepatocyte apoptosis with TNF-α treatment, caspase-3 assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with Smad3 pathway analysis and primary hepatocyte mechanistic follow-up, single lab\",\n      \"pmids\": [\"33396939\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KLF10 (TIEG1) is a TGF-β-inducible Krüppel-like zinc finger transcription factor that binds GC-rich (Sp1/GGTGTG) promoter elements to activate or repress target genes including Smad7, EGFR, SLUG, Bmal1, PEPCK, PGC-1α, RANKL/OPG, Runx2, Osterix, FOXP3, TGF-βRII, IL-9, zDHHC7, and SOST; it represses transcription through recruitment of HDAC1, the histone demethylase JARID1B/KDM5B, and the Sin3-HDAC complex, and activates transcription by associating with PCAF and β-catenin/Lef1; its stability and nuclear localization are regulated post-translationally by RAF-1-mediated phosphorylation at Thr93 (enabling PIN1-isomerase-driven degradation), AMPK-mediated phosphorylation at Thr189 (stabilization), Tyk2-mediated phosphorylation at Tyr179 (promoting K27-polyubiquitination and cytoplasmic retention), and Itch-mediated ubiquitination (nonproteolytic, promoting Foxp3 induction); in bone KLF10 supports osteoblast mineralization and osteoclast differentiation via the RANKL/OPG axis and Wnt/β-catenin signaling, in immune cells it is essential for TGF-β-driven Treg development and suppression of inflammation, and in liver it links the circadian clock to glucose and lipid homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KLF10 (TIEG1) is a TGF-β-inducible Krüppel-like zinc finger transcription factor that translates TGF-β/BMP signaling into transcriptional programs governing cell fate, immune tolerance, bone formation, and hepatic metabolism [#0, #3, #7]. Its zinc finger domain binds GT/GC-rich elements (consensus 5'-GGTGTG-3' and Sp1 sites) in target promoters [#4], and three conserved repressor domains outside the DNA-binding region mediate transcriptional repression [#1]. KLF10 represses targets — including Smad7, EGFR, SLUG/SNAI2, and IL-9 — by occupying their promoters and recruiting HDAC1 to strip activating histone acetylation [#18, #28, #29, #39], and it engages the histone demethylase JARID1B/KDM5B and the Sin3 complex for repression while switching to activation through association with the acetyltransferase PCAF [#15, #24]. As an activator it directly transactivates Runx2 and Osterix to drive osteoblast differentiation [#17, #27] and binds the TGF-βRII promoter in T cells and macrophages to reinforce TGF-β/Smad signaling [#23, #25]. In immune regulation, KLF10 is essential for TGF-β-driven Treg development and suppression of inflammation, acting through a TGF-β1/Foxp3 positive-feedback loop and cooperating with the E3 ligase Itch [#10, #11, #36]. In liver, KLF10 is a circadian-clock-controlled gene that represses Bmal1 and gluconeogenic/lipogenic programs, linking the clock to glucose and lipid homeostasis [#13, #14, #31, #38]. KLF10 stability and localization are set post-translationally by RAF-1/PIN1-driven degradation at Thr93, AMPK-mediated stabilization at Thr189, and Tyk2-mediated Tyr179 phosphorylation that promotes K27-ubiquitination and cytoplasmic retention [#16, #21, #38]. Human KLF10 missense mutations are linked to hypertrophic cardiomyopathy through gain of PTTG1 promoter activation [#44].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established KLF10 as a functional downstream effector of TGF-β rather than a passive marker, by showing its overexpression alone drives apoptosis in TGF-β-sensitive epithelial cells.\",\n      \"evidence\": \"Stable overexpression in PANC1 pancreatic cells with apoptosis readout\",\n      \"pmids\": [\"9153278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define direct transcriptional targets driving apoptosis\", \"Single cell type; mechanism of cell-death induction unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined the molecular grammar of KLF10 as a repressor by mapping three conserved repression domains separate from the DNA-binding region.\",\n      \"evidence\": \"Mutagenesis and GAL4 reporter assays comparing TIEG1 and TIEG2\",\n      \"pmids\": [\"10506214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the corepressors recruited by each domain\", \"Domains defined in heterologous GAL4 context, not native promoters\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved the apoptotic mechanism downstream of KLF10 as mitochondrial/ROS-dependent, showing antioxidant rescue blocks death.\",\n      \"evidence\": \"ROS, mitochondrial potential, caspase, and trolox-rescue assays in Hep3B cells\",\n      \"pmids\": [\"10573529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect ROS generation to a direct transcriptional target\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the DNA-binding specificity of KLF10, anchoring all subsequent promoter-occupancy claims to a GT-rich core motif.\",\n      \"evidence\": \"SELEX-like in vitro selection and mutational analysis of the zinc finger domain\",\n      \"pmids\": [\"12804117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro binding only; in vivo genome-wide occupancy not mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated a physiological bone role in vivo, showing KLF10-null osteoblasts fail BMP2-induced mineralization and dysregulate the RANKL/OPG axis.\",\n      \"evidence\": \"TIEG1 KO calvarial osteoblast culture, mineralization assay, osteoclast co-culture rescue\",\n      \"pmids\": [\"15657444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct promoter targets in osteoblasts not yet identified at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established KLF10 as essential for TGF-β-driven Treg development and immune suppression, and identified Itch as a partner mediating non-proteolytic K63 ubiquitination supporting Foxp3 induction.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, Itch-/- and TIEG1-/- T cells, in vivo airway inflammation\",\n      \"pmids\": [\"18278048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Site of K63 ubiquitination on KLF10 not mapped\", \"How ubiquitination mechanistically enhances Foxp3 transactivation unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined a TGF-β1/Foxp3 positive feedback loop driven by KLF10 promoter transactivation, explaining the Treg suppressor phenotype mechanistically.\",\n      \"evidence\": \"KLF10 KO CD4+ T cell studies, promoter transactivation, Th1/Th2 profiling, atherosclerosis model\",\n      \"pmids\": [\"19602726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors switching KLF10 to activator mode at these promoters not yet defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed KLF10 within the circadian clock and hepatic metabolism, showing it is a CLOCK-BMAL1 target that in turn represses Bmal1 and Pepck to control glucose homeostasis.\",\n      \"evidence\": \"KLF10/Bmal1 KO mice, ChIP at Klf10 promoter, circadian bioluminescence reporters, Pepck reporter, glucose production assay\",\n      \"pmids\": [\"20070857\", \"20385766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KLF10 repression of Bmal1 versus activation of metabolic genes uses distinct cofactors not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the chromatin-modifying machinery for KLF10 repression — the JARID1B/KDM5B demethylase binds the repression domains and augments Smad7 silencing.\",\n      \"evidence\": \"Co-IP, domain mapping, Smad7 reporter with JARID1B gain/loss\",\n      \"pmids\": [\"20863814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"H3K4 demethylation at the Smad7 promoter inferred from reporter data, not directly measured\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established post-translational control of KLF10 function, with Tyk2-mediated Tyr179 phosphorylation triggering K27-ubiquitination and cytoplasmic retention that disables Treg development under inflammatory IL-6.\",\n      \"evidence\": \"Phosphorylation/ubiquitination assays, nuclear fractionation, Treg assays, TRAMP-C2 tumor model\",\n      \"pmids\": [\"21471442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the K27-linkage E3 ligase not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed KLF10 acts both as direct activator (Runx2, p21) and HDAC1-recruiting repressor (EGFR, BI-1), defining its dual transcriptional outputs in bone and cancer.\",\n      \"evidence\": \"ChIP/Co-IP at Runx2 and EGFR promoters, HDAC1 complex Co-IP, ChIP-chip/EMSA at BI-1, KO rescue and xenograft models\",\n      \"pmids\": [\"21559363\", \"22025675\", \"21262377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The determinants that select activation vs repression at a given promoter not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected KLF10 to human disease, showing HCM-associated missense mutations aberrantly raise PTTG1 promoter activity and PTTG1 protein in patient cardiac tissue.\",\n      \"evidence\": \"Site-directed mutagenesis, PTTG1 promoter luciferase, immunohistochemistry of HCM cardiac tissue\",\n      \"pmids\": [\"22234868\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality between mutation and cardiomyopathy not demonstrated by genetic models\", \"Single promoter assayed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a RAF-1/PIN1 degradation axis: phosphorylation at Thr93 creates a pThr93-Pro motif recognized by PIN1 isomerase that drives KLF10 turnover.\",\n      \"evidence\": \"In vitro kinase assay, yeast two-hybrid, Thr93 mutagenesis, cycloheximide chase\",\n      \"pmids\": [\"23994618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase coupling PIN1 isomerization to degradation not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed the molecular switch between KLF10 repression and activation at FOXP3 — an NH2-terminal Sin3-interacting domain restrains activation, and its inactivation enables PCAF recruitment.\",\n      \"evidence\": \"Domain mutagenesis, Co-IP with PCAF and Sin3-HDAC, ChIP, genome-integrated reporter, primary lymphocytes\",\n      \"pmids\": [\"24944246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals that physiologically toggle the Sin3-vs-PCAF balance not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended the TGF-βRII activation mechanism across immune lineages, showing KLF10 promotes TGF-βRII transcription via H3 acetylation to maintain anti-inflammatory macrophage and CD8 T cell signaling.\",\n      \"evidence\": \"ChIP and H3-acetylation assays at TGF-βRII promoter, KO T cells/macrophages, cytokine profiling, adoptive transfer and viral infection models\",\n      \"pmids\": [\"25472963\", \"26472224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The acetyltransferase recruited at TGF-βRII not pinpointed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated KLF10 is itself druggable, with CADD-identified small molecules binding the second zinc finger to block DNA binding and Treg conversion.\",\n      \"evidence\": \"Virtual screening, DNA-binding inhibition assays, Treg conversion assay\",\n      \"pmids\": [\"25581017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No co-crystal structure confirming the predicted pocket\", \"In vivo efficacy not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established KLF10 as a tumor-suppressive brake on EMT and a regulator of Wnt and Smad7 signaling, repressing SLUG and Smad7 via HDAC1 and acting as a β-catenin/Lef1 co-activator in bone.\",\n      \"evidence\": \"ChIP/histone-acetylation at SLUG and Smad7 promoters, Co-IP with β-catenin/Lef1, AKT/GSK-3β assays, KO bone phenotype, clinical specimens\",\n      \"pmids\": [\"28249899\", \"28108300\", \"28201653\", \"26801561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context-dependence of Smad7 repression (pro- vs anti-TGF-β outcomes) across tissues not reconciled\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined KLF10 as a hepatic gluconeogenic driver by directly activating PGC-1α, providing a therapeutic target for hyperglycemia.\",\n      \"evidence\": \"ChIP and luciferase at Pgc-1α promoter, adenoviral gain/loss in hepatocytes and liver, glucose/pyruvate tolerance tests in diabetic mice\",\n      \"pmids\": [\"28836014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration with circadian Pepck regulation not directly addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved KLF10's role in fatty liver disease, showing it activates SREBP-1C-repressive and zDHHC7/CD36-palmitoylation pathways under AMPK control, with opposing lipogenic and protective outcomes.\",\n      \"evidence\": \"AMPK phosphorylation of Thr189, ChIP at SREBP-1C and zDHHC7 promoters, CD36 palmitoylation/membrane fractionation, hepatocyte-specific KO NAFLD/NASH models\",\n      \"pmids\": [\"34869587\", \"35492028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciling KLF10 as both lipogenesis-suppressing (SREBP-1C) and NASH-promoting (zDHHC7/CD36) within one tissue not fully integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked KLF10 in T cells to organ fibrosis, showing it represses IL-9 via HDAC1 and that its loss drives perivascular fibrosis reversible by anti-IL9 antibody.\",\n      \"evidence\": \"ChIP at IL-9 promoter, HDAC1 Co-IP, CD4-specific KO Ang II model, aortic scRNA-seq, antibody rescue\",\n      \"pmids\": [\"35440172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL-9 repression depends on the same TGF-β feedback loop as Foxp3 not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified an exercise-responsive cAMP/PKA/CREB → KLF10 → fumarate hydratase axis that lowers fumarate and H3K4me3 on lipogenic genes to protect against NASH.\",\n      \"evidence\": \"Hepatocyte-specific KO/overexpression mice, treadmill exercise, pathway inhibitors, fumarate metabolomics, H3K4me3 ChIP\",\n      \"pmids\": [\"38615945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Fh1 is a direct KLF10 transcriptional target versus indirect not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KLF10 selects activation versus repression at a given target, and which cofactor/phosphorylation state dictates the choice in each tissue, remains the central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of KLF10 bound to coactivator vs corepressor complexes\", \"No genome-wide occupancy map distinguishing activated vs repressed loci\", \"Logic integrating Thr93/Thr189/Tyr179 phosphomarks with transcriptional output undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 4, 11, 14, 17, 18, 27, 28, 29, 31]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 22, 19]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16, 30]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 11, 23, 29]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 11, 16, 25, 39]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 4, 18, 28, 31]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [14, 31, 37, 38, 40]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [15, 18, 24, 28, 34]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 6, 9, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HDAC1\", \"PCAF\", \"JARID1B\", \"ITCH\", \"PIN1\", \"CTNNB1\", \"LEF1\", \"RUNX2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}