{"gene":"KLF10","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1997,"finding":"Overexpression of KLF10 (TIEG) in TGFβ-sensitive PANC1 pancreatic epithelial cells is sufficient to induce apoptosis, linking TGFβ-mediated signaling to regulation of epithelial cell growth.","method":"Stable transfection/overexpression, cell viability assays","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 — clean OE with defined apoptotic phenotype, single lab","pmids":["9153278"],"is_preprint":false},{"year":1999,"finding":"KLF10 (TIEG1)-induced apoptosis proceeds through generation of reactive oxygen species and loss of mitochondrial membrane potential, followed by caspase-3 activation and glutathione depletion; antioxidant trolox blocks this pathway.","method":"Overexpression in Hep3B cells, ROS measurement, mitochondrial membrane potential assay, caspase activity assay","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway defined with multiple orthogonal assays, single lab","pmids":["10573529"],"is_preprint":false},{"year":1999,"finding":"KLF10 (TIEG1) contains three conserved transcriptional repression domains (R1: 10 aa, R2: 12 aa, R3: ~80 aa) in its N-terminal region outside the zinc finger domain, functionally conserved between TIEG1 and TIEG2.","method":"Extensive mutagenesis, GAL4-based transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis combined with functional transcriptional assays, defining repression domain structure","pmids":["10506214"],"is_preprint":false},{"year":2000,"finding":"Overexpression of KLF10 in human osteosarcoma MG-63 cells mimics TGFβ action: increases alkaline phosphatase activity, decreases osteocalcin mRNA/protein, and decreases cell proliferation; TGFβ treatment adds no further effect.","method":"Stable transfection, gene expression analysis, cell proliferation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — clean OE with multiple phenotypic readouts, single lab","pmids":["10816551"],"is_preprint":false},{"year":2003,"finding":"KLF10 (TIEG/EGRα) binds a consensus GT-rich core sequence (5'-GGTGTG-3') as identified by iterative nitrocellulose filter binding and PCR selection from random oligonucleotide libraries; mutagenesis confirmed this core is necessary for binding.","method":"SELEX (systematic evolution of ligands by exponential enrichment), nitrocellulose filter binding, mutational analysis, VP16 fusion transcriptional assay","journal":"DNA and cell biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical reconstitution with mutagenesis validation","pmids":["12804117"],"is_preprint":false},{"year":2004,"finding":"KLF10 (TIEG1) overexpression in oligodendroglial OLI-neu cells induces apoptosis via repression of Bcl-XL, activation of Smad consensus promoter, and reduction of inhibitory Smad7 promoter activity, thereby facilitating TGFβ-mediated cell death.","method":"Overexpression, apoptosis ELISA, DNA fragmentation, caspase-3 assay, luciferase reporter assays","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple assays defining pathway, single lab","pmids":["14743447"],"is_preprint":false},{"year":2005,"finding":"KLF10 (TIEG1) expression in osteoblasts is required for BMP2-induced mineralization in vitro and for osteoblast support of osteoclast differentiation; KLF10 KO osteoblasts show decreased RANKL and increased OPG expression.","method":"TIEG1 knockout mouse, calvarial osteoblast culture, mineralization assay, co-culture osteoclast differentiation assay, gene expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with multiple defined cellular phenotypes and molecular mechanism, replicated across assays","pmids":["15657444"],"is_preprint":false},{"year":2007,"finding":"KLF10 (TIEG-1) acts as an intermediary factor downstream of BMP2 that blocks N-Myc expression by occupying Sp1 sites in the Nmyc promoter, thereby opposing Shh-mediated proliferation in cerebellar granule cell precursors and inducing cell cycle arrest.","method":"Ectopic expression in cerebellar granular neuron precursors, promoter occupancy analysis, cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter occupancy with functional epistasis, single lab","pmids":["17951258"],"is_preprint":false},{"year":2007,"finding":"KLF10 (TIEG1) induces apoptosis through the mitochondrial pathway involving Bax and Bim upregulation, Bcl-2 and Bcl-XL downregulation, cytochrome c release, caspase-3 activation, and disruption of mitochondrial membrane potential in K562 leukemia cells.","method":"Overexpression, Western blot, mitochondrial membrane potential assay, cytochrome c release assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — multiple mechanistic markers defined, single lab","pmids":["17659279"],"is_preprint":false},{"year":2008,"finding":"The E3 ubiquitin ligase Itch associates with KLF10 (TIEG1) and promotes K63-linked (nonproteolytic) ubiquitination of KLF10; this modification enhances KLF10 function to cooperatively induce Foxp3 expression in TGFβ-treated T cells.","method":"Co-immunoprecipitation, ubiquitination assay, KO mouse studies, in vivo airway inflammation model","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal Co-IP with in vivo functional validation and KO rescue, multiple orthogonal methods","pmids":["18278048"],"is_preprint":false},{"year":2008,"finding":"KLF10 is regulated as a VHL target gene and directly transactivates the TGFBI (BIGH3) promoter in renal clear cell carcinoma cells.","method":"Expression arrays, VHL-status cell lines, luciferase reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — reporter assay in VHL-defined cell lines, single lab","pmids":["18359287"],"is_preprint":false},{"year":2008,"finding":"KLF10 knockout mice (female) display a gender-specific osteopenic phenotype with decreased bone mineral content/density, reduced cortical bone, decreased trabecular number, and reduced bone formation rate, demonstrating an essential role in skeletal homeostasis.","method":"Congenic TIEG-null mouse, DXA, pQCT, micro-CT, 3-point bending tests, histomorphometry","journal":"Bone","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with multiple rigorous bone phenotyping methods","pmids":["18396127"],"is_preprint":false},{"year":2009,"finding":"KLF10 directly transactivates both the TGFβ1 and Foxp3 promoters in CD4+ T cells, creating a positive feedback loop; KLF10-deficient T regulatory cells have reduced TGFβ1 expression and impaired suppressor function, rescuable by exogenous TGFβ1.","method":"KLF10 KO mouse, overexpression, promoter transactivation assays, cytokine measurement, in vivo atherosclerosis model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — KO with epistasis, promoter assays, and in vivo rescue","pmids":["19602726"],"is_preprint":false},{"year":2010,"finding":"KLF10 displays circadian expression in mouse liver driven by the CLOCK-BMAL1 heterodimer binding a conserved E-box in the Klf10 promoter; KLF10 KO mice show dysregulation of metabolic genes, postprandial/fasting hyperglycemia, and KLF10 directly represses the Pepck gluconeogenic gene promoter.","method":"KLF10 KO mouse, chromatin immunoprecipitation (BMAL1 recruitment), liver transcriptome profiling, glucose tolerance tests, luciferase reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP, KO mouse, direct promoter binding, multiple metabolic phenotypes","pmids":["20385766"],"is_preprint":false},{"year":2010,"finding":"KLF10 (TIEG1) represses Bmal1 gene transcription by binding to two juxtaposed GC boxes near the transcription initiation site; siRNA-mediated knockdown of TIEG1 causes period shortening in cellular bioluminescence circadian rhythms.","method":"ChIP, promoter reporter assays, siRNA knockdown, real-time bioluminescence assay","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 1 — direct DNA binding by ChIP with functional period assay","pmids":["20070857"],"is_preprint":false},{"year":2010,"finding":"JARID1B/KDM5B (histone H3K4 demethylase) is a corepressor of KLF10 (TIEG1); the repression domains of KLF10 bind the C-terminus of JARID1B; JARID1B overexpression augments KLF10-mediated Smad7 repression, while JARID1B knockdown increases Smad7 mRNA levels.","method":"Co-immunoprecipitation, domain-binding assays, Smad7 reporter assay, siRNA knockdown","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with functional reporter and KD validation, single lab","pmids":["20863814"],"is_preprint":false},{"year":2011,"finding":"IL-6-induced Tyk2-mediated phosphorylation of KLF10 at Tyr179 promotes non-canonical K27-linked polyubiquitination of KLF10, inhibiting its nuclear translocation and thereby suppressing TGFβ-induced regulatory T cell development.","method":"Phosphorylation mapping, ubiquitination assays (K27-linkage), nuclear translocation assays, KO mouse tumor studies","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — specific PTM site identified with mechanistic consequence and in vivo validation","pmids":["21471442"],"is_preprint":false},{"year":2011,"finding":"KLF10 (TIEG1) directly binds and activates the Runx2 promoter through its zinc finger domain; KLF10 protein also co-immunoprecipitates and co-localizes with Runx2 protein, co-activating Runx2 transcriptional activity; the ubiquitin/proteasome pathway modulates this regulation.","method":"Transient transfection, chromatin immunoprecipitation, co-immunoprecipitation, co-localization assays, KO osteoblasts, adenoviral rescue","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP, Co-IP, domain mutagenesis, KO rescue with multiple orthogonal methods","pmids":["21559363"],"is_preprint":false},{"year":2011,"finding":"KLF10 suppresses EGFR transcription by directly binding the EGFR promoter and forming a complex with HDAC1 at Sp1 sites, leading to reduced histone acetylation and inhibition of breast cancer invasion and metastasis.","method":"ChIP, Co-immunoprecipitation (KLF10-HDAC1 complex), promoter reporter assay, overexpression/knockdown, xenograft model","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP with Co-IP demonstrating complex, in vivo xenograft validation","pmids":["22025675"],"is_preprint":false},{"year":2011,"finding":"KLF10 directly modulates transcription of BI-1 (Bax inhibitor-1) by binding its promoter in estrogen-responsive adenocarcinoma cells; KLF10 suppression of BI-1 increases cytosolic Ca2+ and triggers apoptosis downstream of estrogen signaling.","method":"ChIP-chip, promoter reporter assay, EMSA, siRNA knockdown, Ca2+ measurement","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-chip with EMSA and functional Ca2+ assay, single lab","pmids":["21262377"],"is_preprint":false},{"year":2012,"finding":"KLF10 directly binds the CACCC element of the IL-12p40 promoter and inhibits its transcription in M-CSF-induced macrophages; KLF10 deficiency leads to upregulated IL-12p40 production upon LPS stimulation.","method":"ChIP, promoter reporter assay, KLF10 KO and overexpression, ELISA","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — direct promoter binding by ChIP with KO/OE functional validation","pmids":["23065757"],"is_preprint":false},{"year":2012,"finding":"KLF10 dose-dependently activates p21WAF1/CIP1 transcription independently of p53 and Sp1 binding sites, functioning as a tumor suppressor; KLF10 KO mice show increased susceptibility to skin tumorigenesis after DMBA/TPA treatment.","method":"KO mouse tumor model, luciferase reporter assay, colony formation assay, KLF10 transfection","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — KO in vivo phenotype with direct promoter assay, single lab","pmids":["22349513"],"is_preprint":false},{"year":2013,"finding":"KLF10 binds the proximal Sp factor binding site of the FGFR1 promoter, reduces Sp1 complex formation, and represses FGFR1 promoter activity and myoblast proliferation.","method":"Southwestern blot, EMSA, chromatin immunoprecipitation, promoter reporter assay, cell proliferation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct DNA binding shown by multiple orthogonal methods (EMSA, SW blot, ChIP)","pmids":["23569208"],"is_preprint":false},{"year":2013,"finding":"KLF10 protein stability is regulated by RAF-1-mediated phosphorylation at Thr93, which enables interaction with the prolyl isomerase PIN1 in a phosphorylation-dependent manner, promoting KLF10 protein degradation.","method":"In vivo and in vitro phosphorylation assays, yeast two-hybrid, site-directed mutagenesis, Co-IP, cycloheximide chase","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with mutagenesis and interaction assays identifying specific PTM site and writer","pmids":["23994618"],"is_preprint":false},{"year":2014,"finding":"KLF10 couples to two antagonistic chromatin-modifying complexes to regulate FOXP3 gene inducibility: an N-terminal Sin3-HDAC interacting domain represses FOXP3, while inactivation of this domain allows KLF10 to associate with PCAF histone acetyltransferase and induce FOXP3 transcription.","method":"Chromatin immunoprecipitation, genome-integrated reporter assays, domain deletion/mutation of KLF10, primary lymphocyte assays","journal":"American journal of physiology. Regulatory, integrative and comparative physiology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP with domain mutants and primary cell validation, defining toggle mechanism","pmids":["24944246"],"is_preprint":false},{"year":2014,"finding":"KLF10 directly binds the TGFβRII promoter in CD8+ T cells to enhance its expression; KLF10-deficient CD8+ T cells show reduced TGFβRII surface expression and attenuated Smad2 phosphorylation following TGFβ1 stimulation.","method":"ChIP, KLF10 KO mouse, flow cytometry, Smad2 phosphorylation assay, in vivo viral infection model","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 — ChIP with KO mouse and in vivo validation","pmids":["25472963"],"is_preprint":false},{"year":2015,"finding":"KLF10 directly binds the TGFβRII promoter in colonic macrophages, enhancing TGFβRII gene expression via histone H3 acetylation; KLF10 KO macrophages show lower TGFβRII levels, attenuated Smad-2 phosphorylation, and a pro-inflammatory phenotype.","method":"ChIP, KLF10 KO mouse, histone acetylation assay, cytokine ELISA, bone marrow transfer","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 — ChIP with epigenetic mechanism defined, KO and adoptive transfer validation","pmids":["26472224"],"is_preprint":false},{"year":2015,"finding":"KLF10 transcriptionally activates the SEI-1 promoter, leading to increased SEI-1 and subsequently p21Cip1 expression in pancreatic cells; KLF10 deficiency in mice reduces pancreatic islet mass.","method":"ChIP-chip screening, promoter reporter assay, KLF10 KO mouse histology","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — promoter assay with in vivo KO phenotype, single lab","pmids":["25578559"],"is_preprint":false},{"year":2016,"finding":"KLF10 acts as a transcriptional repressor of NPRA; KLF10 binding reduces NPRA expression, and KLF10-deficient mice show increased pulmonary inflammation and higher sensitivity to LPS/ovalbumin challenge.","method":"ChIP, promoter reporter assay, KLF10 KO mouse, in vivo inflammation model","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP with KO mouse phenotype, single lab","pmids":["27592451"],"is_preprint":false},{"year":2016,"finding":"KLF10 (TIEG1) directly binds and activates the Osterix promoter through its zinc finger domain, mediating TGFβ- and BMP2-induced Osterix expression in osteoblasts; TIEG1 KO osteoblasts have decreased Osterix.","method":"ChIP, transient transfection, domain mutagenesis, KO mouse osteoblasts","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP with domain mutagenesis and KO validation","pmids":["26801561"],"is_preprint":false},{"year":2017,"finding":"KLF10 represses SLUG/SNAI2 transcription by occupying GC-rich sequences in its promoter and recruiting HDAC1 to remove activating histone acetylation marks, thereby suppressing TGFβ-induced epithelial-to-mesenchymal transition.","method":"KLF10 depletion, ChIP, histone modification analysis, EMT assays (multiple metrics), lung adenocarcinoma specimens","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP with HDAC1 recruitment, multiple EMT metrics, clinical validation","pmids":["28249899"],"is_preprint":false},{"year":2017,"finding":"KLF10 directly represses Smad7 transcription by binding a GC-box/Sp1 site (-1392 to -1382) in the Smad7 promoter, thereby promoting Smad2 phosphorylation and TGFβ/Smad signaling in keloid fibroblasts.","method":"ChIP, luciferase reporter assay, siRNA knockdown, TIEG1 overexpression, Western blot","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP with defined binding site + mutagenesis and functional Smad2 readout","pmids":["28108300"],"is_preprint":false},{"year":2017,"finding":"KLF10 activates Pgc-1α gene transcription by directly binding to its promoter region, thereby regulating hepatic gluconeogenesis; KLF10 overexpression increases gluconeogenic gene expression and blood glucose levels.","method":"Luciferase reporter assay, ChIP, adenovirus overexpression/knockdown in mice, glucose tolerance tests","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 1-2 — direct promoter binding by ChIP with in vivo metabolic phenotype","pmids":["28836014"],"is_preprint":false},{"year":2017,"finding":"KLF10 (TIEG1) modulates β-catenin sub-cellular localization by altering AKT and GSK-3β activity; KLF10 also physically interacts with and serves as a transcriptional co-activator for Lef1 and β-catenin in the canonical Wnt signaling pathway in bone.","method":"Co-immunoprecipitation, subcellular fractionation, AKT/GSK-3β activity assays, KO mouse osteoblasts, Wnt reporter","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — Co-IP with functional pathway assays and KO mouse, multiple orthogonal methods","pmids":["28201653"],"is_preprint":false},{"year":2017,"finding":"Loss of KLF10 in pancreatic ductal adenocarcinoma increases distant metastases through activation of SDF-1/CXCR4 and AP-1 pathways; targeting SDF-1/CXCR4 in KLF10-null PDAC suppresses progression.","method":"KLF10 conditional KO mouse (KrasG12D model), in vivo tumor studies, pathway analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO in complex in vivo cancer model with pathway rescue, single lab","pmids":["28581520"],"is_preprint":false},{"year":2018,"finding":"KLF10 is transcriptionally induced by C/EBPβ (which binds the KLF10 promoter) during early adipogenesis; KLF10 then recruits HDAC1 to the C/EBPα promoter, reducing histone H4 acetylation and repressing C/EBPα (and consequently PPARγ) transcription to delay adipogenic gene expression.","method":"ChIP, promoter deletion/mutation analysis, luciferase reporter assay, siRNA, 3T3-L1 differentiation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP with domain analysis, HDAC1 recruitment, and functional differentiation assay","pmids":["30026232"],"is_preprint":false},{"year":2019,"finding":"KDM6A (histone lysine demethylase) upregulates KLF10 expression, which in turn increases KDM6A expression forming a positive feedback loop; KLF10 represses nephrin expression by binding its promoter and recruiting methyltransferase Dnmt1.","method":"ChIP, KDM6A and KLF10 KO mice, Dnmt1 recruitment assay, kidney injury measurements","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP defining KLF10-Dnmt1 promoter complex, KO mice with disease phenotype","pmids":["30948420"],"is_preprint":false},{"year":2019,"finding":"Loss of Tieg1 (KLF10) in mice results in altered sarcomere organization, decreased mitochondrial number, reduced succinate dehydrogenase staining, decreased complex I, COX and citrate synthase activities in soleus muscle, and exercise intolerance.","method":"TIEG1 KO mouse, RNA-seq, electron microscopy, histochemistry, mitochondrial function assays, 31P NMR spectroscopy","journal":"Acta physiologica","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in KO mouse defining mitochondrial mechanism","pmids":["31560161"],"is_preprint":false},{"year":2020,"finding":"CD4+ T-cell-specific KLF10 KO mice develop obesity, insulin resistance, and fatty liver due to impaired CD4+ Treg mobilization; TKO Tregs show reduced mitochondrial respiration, glycolysis, and PI3K-Akt-mTOR signaling causing impaired chemotaxis; adoptive transfer of WT Tregs fully rescues the phenotype.","method":"CD4-specific KO mouse, adoptive transfer, metabolic phenotyping, mitochondrial respiration assay, PI3K-Akt-mTOR pathway analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — cell-specific KO with adoptive transfer rescue and defined metabolic mechanism","pmids":["33378664"],"is_preprint":false},{"year":2021,"finding":"KLF10 transcriptionally activates zDHHC7 expression; zDHHC7-mediated palmitoylation of CD36 promotes its plasma membrane localization, driving hepatic lipid accumulation and inflammation in NASH.","method":"Transcriptomic analysis, hepatocyte-specific KO/overexpression, palmitoylation assay, CD36 membrane localization, diet-induced NASH mouse model","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic chain from KLF10 transcription to palmitoylation and membrane localization, in vivo validation","pmids":["35492028"],"is_preprint":false},{"year":2021,"finding":"AMPK phosphorylates KLF10 at Thr189, stabilizing the protein; phosphorylated KLF10 binds the SREBP-1C promoter to repress its transcription and downstream lipogenesis; hepatic-specific KLF10 KO mice develop more severe NAFLD.","method":"In vitro kinase assay, phosphorylation-site mutagenesis, ChIP-chip, luciferase reporter assay, hepatic-specific KO mouse, NAFLD model","journal":"Frontiers in molecular biosciences","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay with mutagenesis + ChIP + in vivo KO validation","pmids":["34869587"],"is_preprint":false},{"year":2021,"finding":"KLF10 integrates circadian and sugar signaling in hepatocytes; loss of hepatocyte KLF10 reprograms the liver circadian transcriptome altering energy metabolism pathways; glucose/fructose induce Klf10 which mitigates glucose intolerance and hepatic steatosis.","method":"Hepatocyte-specific KLF10 KO, liver circadian transcriptome profiling, metabolic challenge assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — hepatocyte-specific KO with comprehensive transcriptome and in vivo metabolic phenotyping","pmids":["34402428"],"is_preprint":false},{"year":2022,"finding":"KLF10 binds the IL-9 promoter and interacts with HDAC1 to inhibit IL-9 transcription in CD4+ T cells; KLF10 deficiency in T cells elevates IL-9, which activates fibroblast calcium mobilization and promotes perivascular fibrosis.","method":"ChIP (KLF10-IL-9 promoter, HDAC1 interaction), CD4-specific KO mouse, Ang II infusion model, anti-IL9 antibody rescue, scRNA-seq","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP with HDAC1 co-recruitment, in vivo KO with antibody rescue, scRNA-seq","pmids":["35440172"],"is_preprint":false},{"year":2022,"finding":"KLF10 negatively regulates HO-1 gene transcription by directly binding to its promoter in vascular smooth muscle cells exposed to high glucose, thereby increasing ROS generation.","method":"ChIP, dual-luciferase reporter assay, KLF10 OE/KD, ROS measurement","journal":"Journal of ethnopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP with direct promoter binding and functional ROS assay, single lab","pmids":["32738388"],"is_preprint":false},{"year":2024,"finding":"Exercise induces hepatic KLF10 expression through the cAMP/PKA/CREB pathway; KLF10 activates fumarate hydratase 1 (Fh1) expression, reducing fumarate accumulation and H3K4me3 marks on lipogenic gene promoters, thereby attenuating hepatocyte steatosis and NASH.","method":"Hepatocyte-specific KO and OE mice, treadmill exercise model, pathway inhibitors, Fh1 expression assay, H3K4me3 ChIP, NASH dietary model","journal":"Metabolism: clinical and experimental","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic chain from exercise stimulus to KLF10 → Fh1 → epigenetic marks, with hepatocyte-specific KO/OE validation","pmids":["38615945"],"is_preprint":false},{"year":2010,"finding":"HPV-16 oncoprotein E7 physically interacts with KLF10 (TIEG1) by binding its C-terminus, promotes KLF10 ubiquitination and degradation via the proteasomal pathway, and attenuates KLF10-mediated apoptosis.","method":"Yeast two-hybrid, Co-immunoprecipitation, ubiquitination assay, apoptosis assay","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — yeast two-hybrid confirmed by Co-IP with functional degradation and apoptosis assays, single lab","pmids":["20691807"],"is_preprint":false}],"current_model":"KLF10 (TIEG1) is a TGFβ-inducible Krüppel-like zinc finger transcription factor that binds GC-rich/Sp1 sites to repress or activate target gene promoters by recruiting chromatin-modifying corepressors (HDAC1, JARID1B/KDM5B, Sin3) or acting as a coactivator (with PCAF, Lef1/β-catenin); its activity and stability are post-translationally regulated by RAF-1-mediated phosphorylation at Thr93 (enabling PIN1 isomerase-dependent degradation), AMPK-mediated phosphorylation at Thr189 (stabilizing the protein), and Itch/Tyk2-mediated K27- and K63-linked ubiquitination (controlling nuclear localization and nonproteolytic enhancement of function); through these mechanisms KLF10 amplifies TGFβ/Smad signaling (by repressing Smad7 and activating Smad2), regulates immune cell differentiation (Foxp3, TGFβRII, IL-9, IL-12p40), bone homeostasis (Runx2, Osterix, RANKL/OPG, Wnt/β-catenin), circadian metabolic outputs (Bmal1, Pepck, Pgc-1α, SREBP-1C, zDHHC7/CD36), EMT (SLUG repression), and apoptosis (via ROS/mitochondrial pathway, Bcl-2 family, and BI-1)."},"narrative":{"teleology":[{"year":1997,"claim":"Establishing that KLF10 is not merely a TGFβ-responsive marker but a functional effector: overexpression was sufficient to induce apoptosis in TGFβ-sensitive epithelial cells, implicating KLF10 as a mediator of TGFβ growth-inhibitory signaling.","evidence":"Stable transfection and cell viability assays in PANC1 pancreatic cells","pmids":["9153278"],"confidence":"Medium","gaps":["Endogenous loss-of-function not tested","Mechanism of apoptosis induction unknown","Generalizability to other cell types unclear"]},{"year":1999,"claim":"Defining the structural basis for KLF10 transcriptional repression and the apoptotic mechanism: three discrete N-terminal repression domains were mapped, and the apoptosis pathway was shown to proceed through ROS generation, mitochondrial depolarization, and caspase-3 activation.","evidence":"GAL4-based mutagenesis/reporter assays for repression domains; ROS, mitochondrial membrane potential, and caspase assays in Hep3B cells for apoptosis","pmids":["10506214","10573529"],"confidence":"High","gaps":["Corepressor partners for each repression domain unidentified","Endogenous target genes mediating apoptosis unknown"]},{"year":2003,"claim":"Defining the DNA-binding specificity of KLF10: SELEX identified a GT-rich core consensus (5'-GGTGTG-3'), establishing that KLF10 recognizes GC/GT-rich elements distinct from but overlapping with canonical Sp1 sites.","evidence":"Iterative nitrocellulose filter binding/SELEX with mutagenesis validation and VP16 transcriptional assay","pmids":["12804117"],"confidence":"High","gaps":["Genome-wide binding profile not determined","Relationship between GT-rich and GC-rich site usage in vivo unresolved"]},{"year":2005,"claim":"Loss-of-function evidence established KLF10 as essential for bone homeostasis: KLF10 KO osteoblasts failed to mineralize properly and showed altered RANKL/OPG ratio, while female KO mice developed osteopenia with reduced bone formation.","evidence":"TIEG1 knockout mouse with calvarial osteoblast culture, mineralization and co-culture assays; DXA, micro-CT, histomorphometry in congenic null mice","pmids":["15657444","18396127"],"confidence":"High","gaps":["Gender-specific mechanism unexplained","Direct transcriptional targets mediating bone phenotype not yet mapped"]},{"year":2008,"claim":"KLF10 was placed at the center of regulatory T cell biology through two discoveries: Itch-mediated K63-linked ubiquitination enhances KLF10 to induce Foxp3, while IL-6/Tyk2-mediated K27-linked ubiquitination blocks KLF10 nuclear entry—establishing opposing ubiquitin codes that toggle Treg versus effector fate.","evidence":"Co-IP, ubiquitin-linkage-specific assays, KO mouse airway inflammation (Itch/K63); phosphorylation mapping, nuclear translocation assays, KO tumor studies (Tyk2/K27)","pmids":["18278048","21471442"],"confidence":"High","gaps":["Deubiquitinase(s) reversing K63 or K27 chains unknown","Whether both ubiquitin modifications occur on the same KLF10 molecule unclear"]},{"year":2009,"claim":"KLF10 was shown to directly transactivate both TGFβ1 and Foxp3 promoters in CD4+ T cells, creating a positive feedback loop for TGFβ signaling; KLF10-deficient Tregs had impaired suppressor function rescuable by exogenous TGFβ1.","evidence":"KLF10 KO mouse, promoter transactivation assays, cytokine measurement, in vivo atherosclerosis model","pmids":["19602726"],"confidence":"High","gaps":["Chromatin remodeling events at Foxp3 locus during KLF10 binding not characterized","Relative contribution of KLF10 versus other KLFs in Treg function undefined"]},{"year":2010,"claim":"KLF10 was integrated into the circadian clock hierarchy: CLOCK-BMAL1 drives circadian Klf10 expression via E-box elements, and KLF10 in turn represses Bmal1 transcription (forming a secondary feedback loop) and represses the gluconeogenic gene Pepck, linking the clock to hepatic glucose metabolism.","evidence":"ChIP for BMAL1 at Klf10 promoter, ChIP for KLF10 at Bmal1 GC boxes, KO mouse metabolic phenotyping, bioluminescence circadian assays","pmids":["20385766","20070857"],"confidence":"High","gaps":["Full set of clock-controlled KLF10 target genes not mapped","Whether KLF10 feeds back to CLOCK protein levels unknown"]},{"year":2010,"claim":"Identification of corepressor partners for KLF10: JARID1B/KDM5B was shown to bind KLF10 repression domains and augment Smad7 repression, while HPV-16 E7 was found to target KLF10 for proteasomal degradation—revealing both physiological and pathological regulation of KLF10 repressor complexes.","evidence":"Co-IP and domain-binding assays for JARID1B; yeast two-hybrid and Co-IP with ubiquitination/degradation assays for E7","pmids":["20863814","20691807"],"confidence":"Medium","gaps":["Whether JARID1B and HDAC1 co-occupy the same KLF10-target promoters simultaneously untested","HPV E7 interaction not validated by reciprocal endogenous Co-IP","E7-KLF10 interaction not confirmed in HPV-infected primary cells"]},{"year":2011,"claim":"KLF10 was shown to directly regulate key osteogenic (Runx2) and oncogenic (EGFR) targets by recruiting distinct chromatin-modifying complexes: KLF10 co-activates Runx2 through direct promoter binding and protein interaction, while it represses EGFR by recruiting HDAC1 to Sp1 sites, suppressing breast cancer metastasis.","evidence":"ChIP, Co-IP, domain mutagenesis, KO osteoblast rescue for Runx2; ChIP, Co-IP of KLF10-HDAC1, xenograft model for EGFR","pmids":["21559363","22025675"],"confidence":"High","gaps":["Whether KLF10-Runx2 protein interaction is direct or bridged unknown","Full spectrum of HDAC1-dependent KLF10 target genes in breast cancer not defined"]},{"year":2013,"claim":"Post-translational control of KLF10 stability was elucidated: RAF-1 phosphorylates KLF10 at Thr93, which creates a binding motif for PIN1 prolyl isomerase, promoting KLF10 degradation—linking RAS-RAF signaling to TGFβ pathway attenuation.","evidence":"In vitro kinase assay, site-directed mutagenesis, yeast two-hybrid and Co-IP for PIN1, cycloheximide chase","pmids":["23994618"],"confidence":"High","gaps":["E3 ligase mediating PIN1-dependent degradation not identified","Whether other MAPK pathway kinases phosphorylate Thr93 untested"]},{"year":2014,"claim":"The dual-mode chromatin switch mechanism of KLF10 was defined: an intact N-terminal Sin3-HDAC domain enforces repression of Foxp3, but when this domain is inactivated, KLF10 associates with PCAF acetyltransferase to activate Foxp3—explaining how a single transcription factor toggles between repression and activation at the same locus.","evidence":"ChIP, genome-integrated reporter assays, domain deletion/mutation, primary lymphocyte assays","pmids":["24944246"],"confidence":"High","gaps":["Signal that inactivates the Sin3-HDAC domain in vivo not identified","Whether this toggle mechanism applies to non-immune targets unknown"]},{"year":2015,"claim":"KLF10 was established as a master regulator of TGFβ receptor expression in immune cells: direct binding to the TGFβRII promoter enhances receptor levels and Smad2 phosphorylation in both CD8+ T cells and macrophages, with KLF10 deficiency producing pro-inflammatory phenotypes.","evidence":"ChIP in CD8+ T cells and macrophages, KLF10 KO mouse with flow cytometry and cytokine ELISA, in vivo viral infection and bone marrow transfer","pmids":["25472963","26472224"],"confidence":"High","gaps":["Whether KLF10 also regulates TGFβRI expression untested","Mechanism of histone H3 acetylation increase at TGFβRII promoter (which acetyltransferase?) unclear"]},{"year":2017,"claim":"Multiple parallel advances established KLF10 as an anti-EMT factor (repressing SLUG via HDAC1 recruitment), a Wnt pathway co-activator (interacting with Lef1/β-catenin in bone), a metabolic regulator (activating Pgc-1α for gluconeogenesis), and an amplifier of TGFβ signaling (repressing Smad7 at a defined GC-box).","evidence":"ChIP with HDAC1 co-recruitment and EMT metrics for SLUG; Co-IP with Lef1/β-catenin and Wnt reporter for Wnt; ChIP and adenoviral OE/KD in mice for Pgc-1α; ChIP with defined binding site mutagenesis for Smad7","pmids":["28249899","28201653","28836014","28108300"],"confidence":"High","gaps":["Whether SLUG repression and Smad7 repression use the same HDAC1 complex unclear","Wnt co-activator function not tested outside osteoblast context","Relative importance of Pgc-1α versus Pepck repression for gluconeogenic output not resolved"]},{"year":2018,"claim":"KLF10 was positioned in the adipogenic transcriptional cascade: C/EBPβ induces KLF10 early in adipogenesis, and KLF10 then recruits HDAC1 to repress C/EBPα and PPARγ, establishing a temporal brake on differentiation.","evidence":"ChIP for C/EBPβ at KLF10 promoter and KLF10/HDAC1 at C/EBPα promoter, promoter deletion analysis, 3T3-L1 differentiation assay","pmids":["30026232"],"confidence":"High","gaps":["Whether KLF10 also regulates later stages of adipogenesis unknown","In vivo adipose-specific KO phenotype not reported"]},{"year":2020,"claim":"Cell-specific KO demonstrated that T cell-intrinsic KLF10 controls systemic metabolism: CD4-specific KLF10 deletion caused obesity, insulin resistance, and fatty liver through impaired Treg mobilization linked to reduced mitochondrial respiration and PI3K-Akt-mTOR signaling, fully rescued by WT Treg transfer.","evidence":"CD4-specific KO mouse, adoptive transfer rescue, metabolic phenotyping, mitochondrial respiration assay","pmids":["33378664"],"confidence":"High","gaps":["Direct KLF10 transcriptional targets controlling Treg metabolism not identified","Whether KLF10 in other immune subsets contributes to metabolic phenotype untested"]},{"year":2021,"claim":"Two stabilizing/destabilizing post-translational pathways and a new lipogenic mechanism were defined: AMPK phosphorylation at Thr189 stabilizes KLF10 to repress SREBP-1C and suppress lipogenesis, while KLF10 also activates zDHHC7 transcription to drive CD36 palmitoylation and hepatic lipid uptake in NASH; hepatocyte-specific KO confirmed KLF10 integrates circadian and sugar signals for energy metabolism.","evidence":"In vitro kinase assay with Thr189 mutagenesis, ChIP-chip, hepatocyte-specific KO NAFLD model for AMPK/SREBP-1C; transcriptomics, palmitoylation assay, diet-induced NASH model for zDHHC7/CD36; hepatocyte-specific KO circadian transcriptome for circadian integration","pmids":["34869587","35492028","34402428"],"confidence":"High","gaps":["How AMPK-stabilized KLF10 represses SREBP-1C while also activating zDHHC7 (seemingly pro-lipogenic) is paradoxical and unresolved","Whether circadian KLF10 oscillation modulates AMPK phosphorylation unknown"]},{"year":2022,"claim":"KLF10 was identified as a direct repressor of IL-9 in CD4+ T cells via HDAC1 recruitment, with KLF10 deficiency driving IL-9-dependent perivascular fibrosis; separately, KLF10 represses HO-1 in vascular smooth muscle cells under high glucose.","evidence":"ChIP for KLF10 and HDAC1 at IL-9 promoter, CD4-specific KO with Ang II model and anti-IL-9 rescue, scRNA-seq; ChIP and reporter assay with ROS measurement for HO-1","pmids":["35440172","32738388"],"confidence":"High","gaps":["Whether IL-9 repression uses the same Sin3-HDAC complex as other targets unclear","In vivo relevance of HO-1 repression to diabetic vascular disease not confirmed in KO models"]},{"year":2024,"claim":"Exercise-induced KLF10 expression was traced through a cAMP/PKA/CREB pathway to activation of fumarate hydratase 1 (Fh1), which reduces fumarate and H3K4me3 at lipogenic gene promoters, providing a mechanistic link between physical activity and NASH attenuation.","evidence":"Hepatocyte-specific KO and OE mice, treadmill exercise model, pathway inhibitors, Fh1 expression assay, H3K4me3 ChIP, NASH dietary model","pmids":["38615945"],"confidence":"High","gaps":["Whether the Fh1-fumarate-H3K4me3 axis is the dominant mechanism or one of several remains unclear","Long-term exercise studies in KLF10 KO not performed"]},{"year":null,"claim":"Several key mechanistic questions remain: (1) genome-wide binding maps in primary tissues have not been reported, (2) the structural basis for the Sin3-HDAC versus PCAF coactivator switch is undefined, (3) how RAF-1/PIN1-mediated degradation versus AMPK-mediated stabilization are coordinated in real time is unknown, and (4) whether KLF10 PTM codes (phosphorylation, K27/K63-ubiquitination) are integrated combinatorially to control nuclear access and target selection has not been tested.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genome-wide ChIP-seq or CUT&RUN in primary cells published","Structural model of KLF10-corepressor/coactivator toggle unavailable","Combinatorial PTM code logic untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,14,17,18,20,22,30,31,32,40]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,5,12,14,18,20,24,29,30,31,35,40,42]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[16,17,24,30]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,12,16,25,26,31,33]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1,5,8]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[13,32,39,40,41,44]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,12,16,20,25,26,38,42]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[13,14,41]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[15,24,35,44]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,11,17,29,33]}],"complexes":[],"partners":["HDAC1","KDM5B","PCAF","PIN1","ITCH","CTNNB1","LEF1","RUNX2"],"other_free_text":[]},"mechanistic_narrative":"KLF10 (TIEG1) is a TGFβ-inducible Krüppel-like zinc finger transcription factor that functions as a central integrator of TGFβ/BMP, Wnt, circadian, and metabolic signaling by binding GC-rich/Sp1 and GT-rich elements in target gene promoters to either repress or activate transcription [PMID:10506214, PMID:12804117]. KLF10 represses target genes (Smad7, SLUG, EGFR, Bmal1, SREBP-1C, IL-9, C/EBPα) by recruiting HDAC1 or the H3K4 demethylase JARID1B/KDM5B, and activates others (Foxp3, TGFβRII, Runx2, Osterix, Pgc-1α, zDHHC7) through association with PCAF acetyltransferase or Lef1/β-catenin, with the choice between repression and activation governed by an N-terminal Sin3-HDAC interaction domain whose inactivation switches KLF10 to an activating mode [PMID:24944246, PMID:22025675, PMID:20863814, PMID:28249899, PMID:19602726]. Protein stability and nuclear localization are controlled by opposing post-translational modifications: RAF-1 phosphorylation at Thr93 licenses PIN1-mediated degradation, AMPK phosphorylation at Thr189 stabilizes the protein, and Tyk2-mediated phosphorylation at Tyr179 triggers K27-linked ubiquitination that blocks nuclear entry, while Itch-mediated K63-linked ubiquitination enhances KLF10 transcriptional function [PMID:23994618, PMID:34869587, PMID:21471442, PMID:18278048]. Through these mechanisms, KLF10 controls TGFβ signal amplification, regulatory T cell differentiation, bone formation and remodeling, circadian hepatic metabolism and gluconeogenesis, adipogenesis, epithelial-mesenchymal transition, and apoptosis via the mitochondrial ROS/caspase pathway [PMID:20385766, PMID:33378664, PMID:15657444, PMID:34402428, PMID:10573529]."},"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":147,"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":99,"is_preprint":false},{"pmid":"15657444","id":"PMC_15657444","title":"TIEG1 null mouse-derived osteoblasts are defective in mineralization and in support of osteoclast differentiation in vitro.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15657444","citation_count":98,"is_preprint":false},{"pmid":"20385766","id":"PMC_20385766","title":"Kruppel-like factor KLF10 is a link between the circadian clock and metabolism in liver.","date":"2010","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20385766","citation_count":97,"is_preprint":false},{"pmid":"19602726","id":"PMC_19602726","title":"Kruppel-like factor KLF10 targets transforming growth factor-beta1 to regulate CD4(+)CD25(-) T cells and T regulatory cells.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19602726","citation_count":88,"is_preprint":false},{"pmid":"33485367","id":"PMC_33485367","title":"Hypoxic tumour cell-derived exosomal miR-340-5p promotes radioresistance of oesophageal squamous cell carcinoma via KLF10.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33485367","citation_count":87,"is_preprint":false},{"pmid":"10762604","id":"PMC_10762604","title":"TIEG proteins join the Smads as TGF-beta-regulated transcription factors that control pancreatic cell growth.","date":"2000","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10762604","citation_count":78,"is_preprint":false},{"pmid":"29799499","id":"PMC_29799499","title":"KLF10 as a Tumor Suppressor Gene and Its TGF-β Signaling.","date":"2018","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/29799499","citation_count":75,"is_preprint":false},{"pmid":"10816551","id":"PMC_10816551","title":"Overexpression of a nuclear protein, TIEG, mimics transforming growth factor-beta action in human osteoblast cells.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10816551","citation_count":70,"is_preprint":false},{"pmid":"17729309","id":"PMC_17729309","title":"Role of TIEG1 in biological processes and disease states.","date":"2007","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17729309","citation_count":69,"is_preprint":false},{"pmid":"21574058","id":"PMC_21574058","title":"Klf10 and Klf11 as mediators of TGF-beta superfamily signaling.","date":"2011","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/21574058","citation_count":69,"is_preprint":false},{"pmid":"15024015","id":"PMC_15024015","title":"Dual functions of transcription factors, transforming growth factor-beta-inducible early gene (TIEG)2 and Sp3, are mediated by CACCC element and Sp1 sites of human monoamine oxidase (MAO) B gene.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15024015","citation_count":61,"is_preprint":false},{"pmid":"30948420","id":"PMC_30948420","title":"A KDM6A-KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction.","date":"2019","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30948420","citation_count":60,"is_preprint":false},{"pmid":"17951258","id":"PMC_17951258","title":"Bone morphogenetic protein 2 opposes Shh-mediated proliferation in cerebellar granule cells through a TIEG-1-based regulation of Nmyc.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17951258","citation_count":60,"is_preprint":false},{"pmid":"22025675","id":"PMC_22025675","title":"TIEG1 inhibits breast cancer invasion and metastasis by inhibition of epidermal growth factor receptor (EGFR) transcription and the EGFR signaling pathway.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22025675","citation_count":54,"is_preprint":false},{"pmid":"18359287","id":"PMC_18359287","title":"Two novel VHL targets, TGFBI (BIGH3) and its transactivator KLF10, are up-regulated in renal clear cell carcinoma and other tumors.","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18359287","citation_count":54,"is_preprint":false},{"pmid":"16888812","id":"PMC_16888812","title":"TGFbeta inducible early gene-1 (TIEG1) and cardiac hypertrophy: Discovery and characterization of a novel signaling pathway.","date":"2007","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16888812","citation_count":52,"is_preprint":false},{"pmid":"33396939","id":"PMC_33396939","title":"Deletion of KLF10 Leads to Stress-Induced Liver Fibrosis upon High Sucrose Feeding.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33396939","citation_count":50,"is_preprint":false},{"pmid":"28249899","id":"PMC_28249899","title":"Krüppel-like Transcription Factor KLF10 Suppresses TGFβ-Induced Epithelial-to-Mesenchymal Transition via a Negative Feedback Mechanism.","date":"2017","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/28249899","citation_count":50,"is_preprint":false},{"pmid":"20863814","id":"PMC_20863814","title":"Histone demethylase JARID1B/KDM5B is a corepressor of TIEG1/KLF10.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20863814","citation_count":48,"is_preprint":false},{"pmid":"27260002","id":"PMC_27260002","title":"Zinc supplementation induces CD4+CD25+Foxp3+ antigen-specific regulatory T cells and suppresses IFN-γ production by upregulation of Foxp3 and KLF-10 and downregulation of IRF-1.","date":"2016","source":"European journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/27260002","citation_count":47,"is_preprint":false},{"pmid":"17541956","id":"PMC_17541956","title":"Estrogen-TGFbeta cross-talk in bone and other cell types: role of TIEG, Runx2, and other transcription factors.","date":"2008","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17541956","citation_count":45,"is_preprint":false},{"pmid":"28108300","id":"PMC_28108300","title":"TIEG1 Represses Smad7-Mediated Activation of TGF-β1/Smad Signaling in Keloid Pathogenesis.","date":"2017","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/28108300","citation_count":44,"is_preprint":false},{"pmid":"18396127","id":"PMC_18396127","title":"TIEG-null mice display an osteopenic gender-specific phenotype.","date":"2008","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/18396127","citation_count":43,"is_preprint":false},{"pmid":"33378664","id":"PMC_33378664","title":"KLF10 Deficiency in CD4+ T Cells Triggers Obesity, Insulin Resistance, and Fatty Liver.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33378664","citation_count":42,"is_preprint":false},{"pmid":"21471442","id":"PMC_21471442","title":"Noncanonical K27-linked polyubiquitination of TIEG1 regulates Foxp3 expression and tumor growth.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21471442","citation_count":38,"is_preprint":false},{"pmid":"10861837","id":"PMC_10861837","title":"Cytokine-specific induction of the TGF-beta inducible early gene (TIEG): regulation by specific members of the TGF-beta family.","date":"2000","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10861837","citation_count":38,"is_preprint":false},{"pmid":"17659279","id":"PMC_17659279","title":"TIEG1 induces apoptosis through mitochondrial apoptotic pathway and promotes apoptosis induced by homoharringtonine and velcade.","date":"2007","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/17659279","citation_count":38,"is_preprint":false},{"pmid":"23569208","id":"PMC_23569208","title":"Repression of myoblast proliferation and fibroblast growth factor receptor 1 promoter activity by KLF10 protein.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23569208","citation_count":37,"is_preprint":false},{"pmid":"30026232","id":"PMC_30026232","title":"Krüppel-like factor 10 (KLF10) is transactivated by the transcription factor C/EBPβ and involved in early 3T3-L1 preadipocyte differentiation.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30026232","citation_count":36,"is_preprint":false},{"pmid":"21559363","id":"PMC_21559363","title":"TIEG1/KLF10 modulates Runx2 expression and activity in osteoblasts.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21559363","citation_count":36,"is_preprint":false},{"pmid":"21262377","id":"PMC_21262377","title":"Klf10 induces cell apoptosis through modulation of BI-1 expression and Ca2+ homeostasis in estrogen-responding adenocarcinoma cells.","date":"2011","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21262377","citation_count":36,"is_preprint":false},{"pmid":"28836014","id":"PMC_28836014","title":"KLF10 transcription factor regulates hepatic glucose metabolism in mice.","date":"2017","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/28836014","citation_count":34,"is_preprint":false},{"pmid":"20070857","id":"PMC_20070857","title":"Transcriptional repressor TIEG1 regulates Bmal1 gene through GC box and controls circadian clockwork.","date":"2010","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/20070857","citation_count":31,"is_preprint":false},{"pmid":"22349513","id":"PMC_22349513","title":"KLF10, transforming growth factor-β-inducible early gene 1, acts as a tumor suppressor.","date":"2012","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/22349513","citation_count":29,"is_preprint":false},{"pmid":"17689119","id":"PMC_17689119","title":"The role of STAT, AP-1, E-box and TIEG motifs in the regulation of hepcidin by IL-6 and BMP-9: lessons from human HAMP and murine Hamp1 and Hamp2 gene promoters.","date":"2007","source":"Blood cells, molecules & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/17689119","citation_count":29,"is_preprint":false},{"pmid":"28581520","id":"PMC_28581520","title":"KLF10 loss in the pancreas provokes activation of SDF-1 and induces distant metastases of pancreatic ductal adenocarcinoma in the KrasG12D p53flox/flox model.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28581520","citation_count":28,"is_preprint":false},{"pmid":"9721211","id":"PMC_9721211","title":"TGFbeta-inducible early gene (TIEG) also codes for early growth response alpha (EGRalpha): evidence of multiple transcripts from alternate promoters.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9721211","citation_count":27,"is_preprint":false},{"pmid":"14743447","id":"PMC_14743447","title":"TIEG1 facilitates transforming growth factor-beta-mediated apoptosis in the oligodendroglial cell line OLI-neu.","date":"2004","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/14743447","citation_count":27,"is_preprint":false},{"pmid":"26310138","id":"PMC_26310138","title":"Klf10 regulates odontoblast differentiation and mineralization via promoting expression of dentin matrix protein 1 and dentin sialophosphoprotein genes.","date":"2015","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/26310138","citation_count":27,"is_preprint":false},{"pmid":"25472963","id":"PMC_25472963","title":"Krüppel-like factor KLF10 regulates transforming growth factor receptor II expression and TGF-β signaling in CD8+ T lymphocytes.","date":"2014","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25472963","citation_count":27,"is_preprint":false},{"pmid":"35492028","id":"PMC_35492028","title":"KLF10 promotes nonalcoholic steatohepatitis progression through transcriptional activation of zDHHC7.","date":"2022","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/35492028","citation_count":26,"is_preprint":false},{"pmid":"22234868","id":"PMC_22234868","title":"TGFβ-inducible early gene-1 (TIEG1) mutations in hypertrophic cardiomyopathy.","date":"2012","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22234868","citation_count":25,"is_preprint":false},{"pmid":"24944246","id":"PMC_24944246","title":"Differential coupling of KLF10 to Sin3-HDAC and PCAF regulates the inducibility of the FOXP3 gene.","date":"2014","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/24944246","citation_count":25,"is_preprint":false},{"pmid":"23994618","id":"PMC_23994618","title":"Destabilization of KLF10, a tumor suppressor, relies on thr93 phosphorylation and isomerase association.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23994618","citation_count":25,"is_preprint":false},{"pmid":"26472224","id":"PMC_26472224","title":"Krüppel-like factor KLF10 deficiency predisposes to colitis through colonic macrophage dysregulation.","date":"2015","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26472224","citation_count":24,"is_preprint":false},{"pmid":"27736981","id":"PMC_27736981","title":"Impact of TIEG1 Deletion on the Passive Mechanical Properties of Fast and Slow Twitch Skeletal Muscles in Female Mice.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27736981","citation_count":24,"is_preprint":false},{"pmid":"20945337","id":"PMC_20945337","title":"TIEG1 negatively controls the myoblast pool indispensable for fusion during myogenic differentiation of C2C12 cells.","date":"2011","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20945337","citation_count":23,"is_preprint":false},{"pmid":"35440172","id":"PMC_35440172","title":"Perivascular Fibrosis Is Mediated by a KLF10-IL-9 Signaling Axis in CD4+ T Cells.","date":"2022","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/35440172","citation_count":22,"is_preprint":false},{"pmid":"34635142","id":"PMC_34635142","title":"Positive feedback between lncRNA FLVCR1-AS1 and KLF10 may inhibit pancreatic cancer progression via the PTEN/AKT pathway.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/34635142","citation_count":22,"is_preprint":false},{"pmid":"32738388","id":"PMC_32738388","title":"Salvia miltiorrhiza bunge exerts anti-oxidative effects through inhibiting KLF10 expression in vascular smooth muscle cells exposed to high glucose.","date":"2020","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32738388","citation_count":22,"is_preprint":false},{"pmid":"37396542","id":"PMC_37396542","title":"Krüppel-like factor 10 (KLF10) as a critical signaling mediator: Versatile functions in physiological and pathophysiological processes.","date":"2022","source":"Genes & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/37396542","citation_count":21,"is_preprint":false},{"pmid":"14697507","id":"PMC_14697507","title":"Gene structure and evolution of Tieg3, a new member of the Tieg family of proteins.","date":"2004","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/14697507","citation_count":21,"is_preprint":false},{"pmid":"28201653","id":"PMC_28201653","title":"TIEG1 modulates β-catenin sub-cellular localization and enhances Wnt signaling in bone.","date":"2017","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/28201653","citation_count":21,"is_preprint":false},{"pmid":"34402428","id":"PMC_34402428","title":"KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34402428","citation_count":20,"is_preprint":false},{"pmid":"33559506","id":"PMC_33559506","title":"MicroRNA-26b-5p alleviates cerebral ischemia-reperfusion injury in rats via inhibiting the N-myc/PTEN axis by downregulating KLF10 expression.","date":"2021","source":"Human & experimental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/33559506","citation_count":20,"is_preprint":false},{"pmid":"26801561","id":"PMC_26801561","title":"TIEG1 enhances Osterix expression and mediates its induction by TGFβ and BMP2 in osteoblasts.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26801561","citation_count":20,"is_preprint":false},{"pmid":"32549754","id":"PMC_32549754","title":"KLF10 inhibits cell growth by regulating PTTG1 in multiple myeloma under the regulation of microRNA-106b-5p.","date":"2020","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32549754","citation_count":20,"is_preprint":false},{"pmid":"23065757","id":"PMC_23065757","title":"Klf10 inhibits IL-12p40 production in macrophage colony-stimulating factor-induced mouse bone marrow-derived macrophages.","date":"2012","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23065757","citation_count":20,"is_preprint":false},{"pmid":"36770589","id":"PMC_36770589","title":"Inhibition of Klf10 Attenuates Oxidative Stress-Induced Senescence of Chondrocytes via Modulating Mitophagy.","date":"2023","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36770589","citation_count":19,"is_preprint":false},{"pmid":"34869587","id":"PMC_34869587","title":"Therapeutic Targeting of Nonalcoholic Fatty Liver Disease by Downregulating SREBP-1C Expression via AMPK-KLF10 Axis.","date":"2021","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/34869587","citation_count":18,"is_preprint":false},{"pmid":"38205211","id":"PMC_38205211","title":"Exosomal ITGB6 from dormant lung adenocarcinoma cells activates cancer-associated fibroblasts by KLF10 positive feedback loop and the TGF-β pathway.","date":"2023","source":"Translational lung cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/38205211","citation_count":18,"is_preprint":false},{"pmid":"29953651","id":"PMC_29953651","title":"MicroRNA-19 restores vascular endothelial cell function in lower limb ischemia-reperfusion injury through the KLF10-dependent TGF-β1/Smad signaling pathway in rats.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29953651","citation_count":18,"is_preprint":false},{"pmid":"31560161","id":"PMC_31560161","title":"Novel role of Tieg1 in muscle metabolism and mitochondrial oxidative capacities.","date":"2019","source":"Acta physiologica (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/31560161","citation_count":17,"is_preprint":false},{"pmid":"38615945","id":"PMC_38615945","title":"Hepatic Klf10-Fh1 axis promotes exercise-mediated amelioration of NASH in mice.","date":"2024","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/38615945","citation_count":17,"is_preprint":false},{"pmid":"27592451","id":"PMC_27592451","title":"Klf10 deficiency in mice exacerbates pulmonary inflammation by increasing expression of the proinflammatory molecule NPRA.","date":"2016","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27592451","citation_count":17,"is_preprint":false},{"pmid":"17931948","id":"PMC_17931948","title":"Minor contribution of SMAD7 and KLF10 variants to genetic susceptibility of type 2 diabetes.","date":"2007","source":"Diabetes & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17931948","citation_count":17,"is_preprint":false},{"pmid":"28204828","id":"PMC_28204828","title":"TIEG1 deficiency confers enhanced myocardial protection in the infarcted heart by mediating the Pten/Akt signalling pathway.","date":"2017","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28204828","citation_count":17,"is_preprint":false},{"pmid":"18798273","id":"PMC_18798273","title":"Bone marrow stroma cells regulate TIEG1 expression in acute lymphoblastic leukemia cells: role of TGFbeta/BMP-6 and TIEG1 in chemotherapy escape.","date":"2008","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/18798273","citation_count":17,"is_preprint":false},{"pmid":"21494610","id":"PMC_21494610","title":"Drosophila TIEG is a modulator of different signalling pathways involved in wing patterning and cell proliferation.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21494610","citation_count":16,"is_preprint":false},{"pmid":"25578559","id":"PMC_25578559","title":"KLF10 affects pancreatic function via the SEI-1/p21Cip1 pathway.","date":"2015","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25578559","citation_count":16,"is_preprint":false},{"pmid":"22563190","id":"PMC_22563190","title":"Transactivation of the TIEG1 confers growth inhibition of transforming growth factor-β-susceptible hepatocellular carcinoma cells.","date":"2012","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/22563190","citation_count":16,"is_preprint":false},{"pmid":"12788480","id":"PMC_12788480","title":"Nitric oxide-mediated upregulation of the TGF-beta-inducible early response gene-1 (TIEG1) in human fibroblasts by mRNA stabilization independent of TGF-beta.","date":"2003","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12788480","citation_count":16,"is_preprint":false},{"pmid":"32699233","id":"PMC_32699233","title":"MCD diet-induced steatohepatitis generates a diurnal rhythm of associated biomarkers and worsens liver injury in Klf10 deficient mice.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32699233","citation_count":15,"is_preprint":false},{"pmid":"25581017","id":"PMC_25581017","title":"Discovery of small molecule inhibitors to Krüppel-like factor 10 (KLF10): implications for modulation of T regulatory cell differentiation.","date":"2015","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25581017","citation_count":15,"is_preprint":false},{"pmid":"27421714","id":"PMC_27421714","title":"Impact of TIEG1 on the structural properties of fast- and slow-twitch skeletal muscle.","date":"2016","source":"Muscle & nerve","url":"https://pubmed.ncbi.nlm.nih.gov/27421714","citation_count":14,"is_preprint":false},{"pmid":"12804117","id":"PMC_12804117","title":"Identification and characterization of a consensus DNA binding element for the zinc finger transcription factor TIEG/EGRalpha.","date":"2003","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12804117","citation_count":14,"is_preprint":false},{"pmid":"25867342","id":"PMC_25867342","title":"Effect of TIEG1 on apoptosis and expression of Bcl-2/Bax and Pten in leukemic cell lines.","date":"2015","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/25867342","citation_count":14,"is_preprint":false},{"pmid":"20155803","id":"PMC_20155803","title":"Tieg1/Klf10 is upregulated by NGF and attenuates cell cycle progression in the pheochromocytoma cell line PC12.","date":"2010","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/20155803","citation_count":14,"is_preprint":false},{"pmid":"32144802","id":"PMC_32144802","title":"KLF10 is a modulatory factor of chondrocyte hypertrophy in developing skeleton.","date":"2020","source":"Journal of orthopaedic research : official publication of the Orthopaedic Research Society","url":"https://pubmed.ncbi.nlm.nih.gov/32144802","citation_count":14,"is_preprint":false},{"pmid":"20171187","id":"PMC_20171187","title":"Possible role of TIEG1 as a feedback regulator of myostatin and TGF-beta in myoblasts.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20171187","citation_count":13,"is_preprint":false},{"pmid":"36174463","id":"PMC_36174463","title":"KLF10 deficiency in CD4+ T cells promotes atherosclerosis progression by altering macrophage dynamics.","date":"2022","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/36174463","citation_count":13,"is_preprint":false},{"pmid":"32156482","id":"PMC_32156482","title":"KLF10 is upregulated in osteoarthritis and inhibits chondrocyte proliferation and migration by upregulating Acvr1 and suppressing inhbb expression.","date":"2020","source":"Acta histochemica","url":"https://pubmed.ncbi.nlm.nih.gov/32156482","citation_count":13,"is_preprint":false},{"pmid":"27488034","id":"PMC_27488034","title":"KLF10 Mediated Epigenetic Dysregulation of Epithelial CD40/CD154 Promotes Endometriosis.","date":"2016","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/27488034","citation_count":13,"is_preprint":false},{"pmid":"35497935","id":"PMC_35497935","title":"KLF10 upregulates ACSM3 via the PI3K/Akt signaling pathway to inhibit the malignant progression of melanoma.","date":"2022","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/35497935","citation_count":12,"is_preprint":false},{"pmid":"34805140","id":"PMC_34805140","title":"Effect of Photodynamic Therapy on Gemcitabine-Resistant Cholangiocarcinoma in vitro and in vivo Through KLF10 and EGFR.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34805140","citation_count":12,"is_preprint":false},{"pmid":"20378701","id":"PMC_20378701","title":"Molecular structure of tail tendon fibers in TIEG1 knockout mice using synchrotron diffraction technology.","date":"2010","source":"Journal of applied physiology (Bethesda, Md. : 1985)","url":"https://pubmed.ncbi.nlm.nih.gov/20378701","citation_count":12,"is_preprint":false},{"pmid":"31284128","id":"PMC_31284128","title":"miR-892b Inhibits Hypertrophy by Targeting KLF10 in the Chondrogenesis of Mesenchymal Stem Cells.","date":"2019","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/31284128","citation_count":12,"is_preprint":false},{"pmid":"28085748","id":"PMC_28085748","title":"Klf10 Gene, a Secondary Modifier and a Pharmacogenomic Biomarker of Hydroxyurea Treatment Among Patients With Hemoglobinopathies.","date":"2017","source":"Journal of pediatric hematology/oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28085748","citation_count":11,"is_preprint":false},{"pmid":"35565995","id":"PMC_35565995","title":"Knockout of KLF10 Ameliorated Diabetic Renal Fibrosis via Downregulation of DKK-1.","date":"2022","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35565995","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":"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},{"pmid":"36445338","id":"PMC_36445338","title":"LINC00629, a KLF10-responsive lncRNA, promotes the anticancer effects of apigenin by decreasing Mcl1 stability in oral squamous cell carcinoma.","date":"2022","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/36445338","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":"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":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50556,"output_tokens":9848,"usd":0.149694},"stage2":{"model":"claude-opus-4-6","input_tokens":13940,"output_tokens":5561,"usd":0.313088},"total_usd":0.462782,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Overexpression of KLF10 (TIEG) in TGFβ-sensitive PANC1 pancreatic epithelial cells is sufficient to induce apoptosis, linking TGFβ-mediated signaling to regulation of epithelial cell growth.\",\n      \"method\": \"Stable transfection/overexpression, cell viability assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean OE with defined apoptotic phenotype, single lab\",\n      \"pmids\": [\"9153278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"KLF10 (TIEG1)-induced apoptosis proceeds through generation of reactive oxygen species and loss of mitochondrial membrane potential, followed by caspase-3 activation and glutathione depletion; antioxidant trolox blocks this pathway.\",\n      \"method\": \"Overexpression in Hep3B cells, ROS measurement, mitochondrial membrane potential assay, caspase activity assay\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway defined with multiple orthogonal assays, single lab\",\n      \"pmids\": [\"10573529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"KLF10 (TIEG1) contains three conserved transcriptional repression domains (R1: 10 aa, R2: 12 aa, R3: ~80 aa) in its N-terminal region outside the zinc finger domain, functionally conserved between TIEG1 and TIEG2.\",\n      \"method\": \"Extensive mutagenesis, GAL4-based transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis combined with functional transcriptional assays, defining repression domain structure\",\n      \"pmids\": [\"10506214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Overexpression of KLF10 in human osteosarcoma MG-63 cells mimics TGFβ action: increases alkaline phosphatase activity, decreases osteocalcin mRNA/protein, and decreases cell proliferation; TGFβ treatment adds no further effect.\",\n      \"method\": \"Stable transfection, gene expression analysis, cell proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean OE with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"10816551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"KLF10 (TIEG/EGRα) binds a consensus GT-rich core sequence (5'-GGTGTG-3') as identified by iterative nitrocellulose filter binding and PCR selection from random oligonucleotide libraries; mutagenesis confirmed this core is necessary for binding.\",\n      \"method\": \"SELEX (systematic evolution of ligands by exponential enrichment), nitrocellulose filter binding, mutational analysis, VP16 fusion transcriptional assay\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical reconstitution with mutagenesis validation\",\n      \"pmids\": [\"12804117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KLF10 (TIEG1) overexpression in oligodendroglial OLI-neu cells induces apoptosis via repression of Bcl-XL, activation of Smad consensus promoter, and reduction of inhibitory Smad7 promoter activity, thereby facilitating TGFβ-mediated cell death.\",\n      \"method\": \"Overexpression, apoptosis ELISA, DNA fragmentation, caspase-3 assay, luciferase reporter assays\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple assays defining pathway, single lab\",\n      \"pmids\": [\"14743447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KLF10 (TIEG1) expression in osteoblasts is required for BMP2-induced mineralization in vitro and for osteoblast support of osteoclast differentiation; KLF10 KO osteoblasts show decreased RANKL and increased OPG expression.\",\n      \"method\": \"TIEG1 knockout mouse, calvarial osteoblast culture, mineralization assay, co-culture osteoclast differentiation assay, gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with multiple defined cellular phenotypes and molecular mechanism, replicated across assays\",\n      \"pmids\": [\"15657444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KLF10 (TIEG-1) acts as an intermediary factor downstream of BMP2 that blocks N-Myc expression by occupying Sp1 sites in the Nmyc promoter, thereby opposing Shh-mediated proliferation in cerebellar granule cell precursors and inducing cell cycle arrest.\",\n      \"method\": \"Ectopic expression in cerebellar granular neuron precursors, promoter occupancy analysis, cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter occupancy with functional epistasis, single lab\",\n      \"pmids\": [\"17951258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KLF10 (TIEG1) induces apoptosis through the mitochondrial pathway involving Bax and Bim upregulation, Bcl-2 and Bcl-XL downregulation, cytochrome c release, caspase-3 activation, and disruption of mitochondrial membrane potential in K562 leukemia cells.\",\n      \"method\": \"Overexpression, Western blot, mitochondrial membrane potential assay, cytochrome c release assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mechanistic markers defined, single lab\",\n      \"pmids\": [\"17659279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The E3 ubiquitin ligase Itch associates with KLF10 (TIEG1) and promotes K63-linked (nonproteolytic) ubiquitination of KLF10; this modification enhances KLF10 function to cooperatively induce Foxp3 expression in TGFβ-treated T cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, KO mouse studies, in vivo airway inflammation model\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP with in vivo functional validation and KO rescue, multiple orthogonal methods\",\n      \"pmids\": [\"18278048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KLF10 is regulated as a VHL target gene and directly transactivates the TGFBI (BIGH3) promoter in renal clear cell carcinoma cells.\",\n      \"method\": \"Expression arrays, VHL-status cell lines, luciferase reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reporter assay in VHL-defined cell lines, single lab\",\n      \"pmids\": [\"18359287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KLF10 knockout mice (female) display a gender-specific osteopenic phenotype with decreased bone mineral content/density, reduced cortical bone, decreased trabecular number, and reduced bone formation rate, demonstrating an essential role in skeletal homeostasis.\",\n      \"method\": \"Congenic TIEG-null mouse, DXA, pQCT, micro-CT, 3-point bending tests, histomorphometry\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with multiple rigorous bone phenotyping methods\",\n      \"pmids\": [\"18396127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KLF10 directly transactivates both the TGFβ1 and Foxp3 promoters in CD4+ T cells, creating a positive feedback loop; KLF10-deficient T regulatory cells have reduced TGFβ1 expression and impaired suppressor function, rescuable by exogenous TGFβ1.\",\n      \"method\": \"KLF10 KO mouse, overexpression, promoter transactivation assays, cytokine measurement, in vivo atherosclerosis model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with epistasis, promoter assays, and in vivo rescue\",\n      \"pmids\": [\"19602726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KLF10 displays circadian expression in mouse liver driven by the CLOCK-BMAL1 heterodimer binding a conserved E-box in the Klf10 promoter; KLF10 KO mice show dysregulation of metabolic genes, postprandial/fasting hyperglycemia, and KLF10 directly represses the Pepck gluconeogenic gene promoter.\",\n      \"method\": \"KLF10 KO mouse, chromatin immunoprecipitation (BMAL1 recruitment), liver transcriptome profiling, glucose tolerance tests, luciferase reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP, KO mouse, direct promoter binding, multiple metabolic phenotypes\",\n      \"pmids\": [\"20385766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KLF10 (TIEG1) represses Bmal1 gene transcription by binding to two juxtaposed GC boxes near the transcription initiation site; siRNA-mediated knockdown of TIEG1 causes period shortening in cellular bioluminescence circadian rhythms.\",\n      \"method\": \"ChIP, promoter reporter assays, siRNA knockdown, real-time bioluminescence assay\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct DNA binding by ChIP with functional period assay\",\n      \"pmids\": [\"20070857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"JARID1B/KDM5B (histone H3K4 demethylase) is a corepressor of KLF10 (TIEG1); the repression domains of KLF10 bind the C-terminus of JARID1B; JARID1B overexpression augments KLF10-mediated Smad7 repression, while JARID1B knockdown increases Smad7 mRNA levels.\",\n      \"method\": \"Co-immunoprecipitation, domain-binding assays, Smad7 reporter assay, siRNA knockdown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with functional reporter and KD validation, single lab\",\n      \"pmids\": [\"20863814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-6-induced Tyk2-mediated phosphorylation of KLF10 at Tyr179 promotes non-canonical K27-linked polyubiquitination of KLF10, inhibiting its nuclear translocation and thereby suppressing TGFβ-induced regulatory T cell development.\",\n      \"method\": \"Phosphorylation mapping, ubiquitination assays (K27-linkage), nuclear translocation assays, KO mouse tumor studies\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — specific PTM site identified with mechanistic consequence and in vivo validation\",\n      \"pmids\": [\"21471442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KLF10 (TIEG1) directly binds and activates the Runx2 promoter through its zinc finger domain; KLF10 protein also co-immunoprecipitates and co-localizes with Runx2 protein, co-activating Runx2 transcriptional activity; the ubiquitin/proteasome pathway modulates this regulation.\",\n      \"method\": \"Transient transfection, chromatin immunoprecipitation, co-immunoprecipitation, co-localization assays, KO osteoblasts, adenoviral rescue\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP, Co-IP, domain mutagenesis, KO rescue with multiple orthogonal methods\",\n      \"pmids\": [\"21559363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KLF10 suppresses EGFR transcription by directly binding the EGFR promoter and forming a complex with HDAC1 at Sp1 sites, leading to reduced histone acetylation and inhibition of breast cancer invasion and metastasis.\",\n      \"method\": \"ChIP, Co-immunoprecipitation (KLF10-HDAC1 complex), promoter reporter assay, overexpression/knockdown, xenograft model\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP with Co-IP demonstrating complex, in vivo xenograft validation\",\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 its promoter in estrogen-responsive adenocarcinoma cells; KLF10 suppression of BI-1 increases cytosolic Ca2+ and triggers apoptosis downstream of estrogen signaling.\",\n      \"method\": \"ChIP-chip, promoter reporter assay, EMSA, siRNA knockdown, Ca2+ measurement\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-chip with EMSA and functional Ca2+ assay, single lab\",\n      \"pmids\": [\"21262377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KLF10 directly binds the CACCC element of the IL-12p40 promoter and inhibits its transcription in M-CSF-induced macrophages; KLF10 deficiency leads to upregulated IL-12p40 production upon LPS stimulation.\",\n      \"method\": \"ChIP, promoter reporter assay, KLF10 KO and overexpression, ELISA\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct promoter binding by ChIP with KO/OE functional validation\",\n      \"pmids\": [\"23065757\"],\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, functioning as a tumor suppressor; KLF10 KO mice show increased susceptibility to skin tumorigenesis after DMBA/TPA treatment.\",\n      \"method\": \"KO mouse tumor model, luciferase reporter assay, colony formation assay, KLF10 transfection\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO in vivo phenotype with direct promoter assay, single lab\",\n      \"pmids\": [\"22349513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KLF10 binds the proximal Sp factor binding site of the FGFR1 promoter, reduces Sp1 complex formation, and represses FGFR1 promoter activity and myoblast proliferation.\",\n      \"method\": \"Southwestern blot, EMSA, chromatin immunoprecipitation, promoter reporter assay, cell proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct DNA binding shown by multiple orthogonal methods (EMSA, SW blot, ChIP)\",\n      \"pmids\": [\"23569208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KLF10 protein stability is regulated by RAF-1-mediated phosphorylation at Thr93, which enables interaction with the prolyl isomerase PIN1 in a phosphorylation-dependent manner, promoting KLF10 protein degradation.\",\n      \"method\": \"In vivo and in vitro phosphorylation assays, yeast two-hybrid, site-directed mutagenesis, Co-IP, cycloheximide chase\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis and interaction assays identifying specific PTM site and writer\",\n      \"pmids\": [\"23994618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KLF10 couples to two antagonistic chromatin-modifying complexes to regulate FOXP3 gene inducibility: an N-terminal Sin3-HDAC interacting domain represses FOXP3, while inactivation of this domain allows KLF10 to associate with PCAF histone acetyltransferase and induce FOXP3 transcription.\",\n      \"method\": \"Chromatin immunoprecipitation, genome-integrated reporter assays, domain deletion/mutation of KLF10, primary lymphocyte assays\",\n      \"journal\": \"American journal of physiology. Regulatory, integrative and comparative physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP with domain mutants and primary cell validation, defining toggle mechanism\",\n      \"pmids\": [\"24944246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KLF10 directly binds the TGFβRII promoter in CD8+ T cells to enhance its expression; KLF10-deficient CD8+ T cells show reduced TGFβRII surface expression and attenuated Smad2 phosphorylation following TGFβ1 stimulation.\",\n      \"method\": \"ChIP, KLF10 KO mouse, flow cytometry, Smad2 phosphorylation assay, in vivo viral infection model\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP with KO mouse and in vivo validation\",\n      \"pmids\": [\"25472963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KLF10 directly binds the TGFβRII promoter in colonic macrophages, enhancing TGFβRII gene expression via histone H3 acetylation; KLF10 KO macrophages show lower TGFβRII levels, attenuated Smad-2 phosphorylation, and a pro-inflammatory phenotype.\",\n      \"method\": \"ChIP, KLF10 KO mouse, histone acetylation assay, cytokine ELISA, bone marrow transfer\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP with epigenetic mechanism defined, KO and adoptive transfer validation\",\n      \"pmids\": [\"26472224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KLF10 transcriptionally activates the SEI-1 promoter, leading to increased SEI-1 and subsequently p21Cip1 expression in pancreatic cells; KLF10 deficiency in mice reduces pancreatic islet mass.\",\n      \"method\": \"ChIP-chip screening, promoter reporter assay, KLF10 KO mouse histology\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter assay with in vivo KO phenotype, single lab\",\n      \"pmids\": [\"25578559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KLF10 acts as a transcriptional repressor of NPRA; KLF10 binding reduces NPRA expression, and KLF10-deficient mice show increased pulmonary inflammation and higher sensitivity to LPS/ovalbumin challenge.\",\n      \"method\": \"ChIP, promoter reporter assay, KLF10 KO mouse, in vivo inflammation model\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP with KO mouse phenotype, single lab\",\n      \"pmids\": [\"27592451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KLF10 (TIEG1) directly binds and activates the Osterix promoter through its zinc finger domain, mediating TGFβ- and BMP2-induced Osterix expression in osteoblasts; TIEG1 KO osteoblasts have decreased Osterix.\",\n      \"method\": \"ChIP, transient transfection, domain mutagenesis, KO mouse osteoblasts\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP with domain mutagenesis and KO validation\",\n      \"pmids\": [\"26801561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KLF10 represses SLUG/SNAI2 transcription by occupying GC-rich sequences in its promoter and recruiting HDAC1 to remove activating histone acetylation marks, thereby suppressing TGFβ-induced epithelial-to-mesenchymal transition.\",\n      \"method\": \"KLF10 depletion, ChIP, histone modification analysis, EMT assays (multiple metrics), lung adenocarcinoma specimens\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP with HDAC1 recruitment, multiple EMT metrics, clinical validation\",\n      \"pmids\": [\"28249899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KLF10 directly represses Smad7 transcription by binding a GC-box/Sp1 site (-1392 to -1382) in the Smad7 promoter, thereby promoting Smad2 phosphorylation and TGFβ/Smad signaling in keloid fibroblasts.\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA knockdown, TIEG1 overexpression, Western blot\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP with defined binding site + mutagenesis and functional Smad2 readout\",\n      \"pmids\": [\"28108300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KLF10 activates Pgc-1α gene transcription by directly binding to its promoter region, thereby regulating hepatic gluconeogenesis; KLF10 overexpression increases gluconeogenic gene expression and blood glucose levels.\",\n      \"method\": \"Luciferase reporter assay, ChIP, adenovirus overexpression/knockdown in mice, glucose tolerance tests\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct promoter binding by ChIP with in vivo metabolic phenotype\",\n      \"pmids\": [\"28836014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KLF10 (TIEG1) modulates β-catenin sub-cellular localization by altering AKT and GSK-3β activity; KLF10 also physically interacts with and serves as a transcriptional co-activator for Lef1 and β-catenin in the canonical Wnt signaling pathway in bone.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, AKT/GSK-3β activity assays, KO mouse osteoblasts, Wnt reporter\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with functional pathway assays and KO mouse, multiple orthogonal methods\",\n      \"pmids\": [\"28201653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of KLF10 in pancreatic ductal adenocarcinoma increases distant metastases through activation of SDF-1/CXCR4 and AP-1 pathways; targeting SDF-1/CXCR4 in KLF10-null PDAC suppresses progression.\",\n      \"method\": \"KLF10 conditional KO mouse (KrasG12D model), in vivo tumor studies, pathway analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in complex in vivo cancer model with pathway rescue, single lab\",\n      \"pmids\": [\"28581520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KLF10 is transcriptionally induced by C/EBPβ (which binds the KLF10 promoter) during early adipogenesis; KLF10 then recruits HDAC1 to the C/EBPα promoter, reducing histone H4 acetylation and repressing C/EBPα (and consequently PPARγ) transcription to delay adipogenic gene expression.\",\n      \"method\": \"ChIP, promoter deletion/mutation analysis, luciferase reporter assay, siRNA, 3T3-L1 differentiation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP with domain analysis, HDAC1 recruitment, and functional differentiation assay\",\n      \"pmids\": [\"30026232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM6A (histone lysine demethylase) upregulates KLF10 expression, which in turn increases KDM6A expression forming a positive feedback loop; KLF10 represses nephrin expression by binding its promoter and recruiting methyltransferase Dnmt1.\",\n      \"method\": \"ChIP, KDM6A and KLF10 KO mice, Dnmt1 recruitment assay, kidney injury measurements\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP defining KLF10-Dnmt1 promoter complex, KO mice with disease phenotype\",\n      \"pmids\": [\"30948420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of Tieg1 (KLF10) in mice results in altered sarcomere organization, decreased mitochondrial number, reduced succinate dehydrogenase staining, decreased complex I, COX and citrate synthase activities in soleus muscle, and exercise intolerance.\",\n      \"method\": \"TIEG1 KO mouse, RNA-seq, electron microscopy, histochemistry, mitochondrial function assays, 31P NMR spectroscopy\",\n      \"journal\": \"Acta physiologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in KO mouse defining mitochondrial mechanism\",\n      \"pmids\": [\"31560161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD4+ T-cell-specific KLF10 KO mice develop obesity, insulin resistance, and fatty liver due to impaired CD4+ Treg mobilization; TKO Tregs show reduced mitochondrial respiration, glycolysis, and PI3K-Akt-mTOR signaling causing impaired chemotaxis; adoptive transfer of WT Tregs fully rescues the phenotype.\",\n      \"method\": \"CD4-specific KO mouse, adoptive transfer, metabolic phenotyping, mitochondrial respiration assay, PI3K-Akt-mTOR pathway analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-specific KO with adoptive transfer rescue and defined metabolic mechanism\",\n      \"pmids\": [\"33378664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KLF10 transcriptionally activates zDHHC7 expression; zDHHC7-mediated palmitoylation of CD36 promotes its plasma membrane localization, driving hepatic lipid accumulation and inflammation in NASH.\",\n      \"method\": \"Transcriptomic analysis, hepatocyte-specific KO/overexpression, palmitoylation assay, CD36 membrane localization, diet-induced NASH mouse model\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic chain from KLF10 transcription to palmitoylation and membrane localization, in vivo validation\",\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 to repress its transcription and downstream lipogenesis; hepatic-specific KLF10 KO mice develop more severe NAFLD.\",\n      \"method\": \"In vitro kinase assay, phosphorylation-site mutagenesis, ChIP-chip, luciferase reporter assay, hepatic-specific KO mouse, NAFLD model\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis + ChIP + in vivo KO validation\",\n      \"pmids\": [\"34869587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KLF10 integrates circadian and sugar signaling in hepatocytes; loss of hepatocyte KLF10 reprograms the liver circadian transcriptome altering energy metabolism pathways; glucose/fructose induce Klf10 which mitigates glucose intolerance and hepatic steatosis.\",\n      \"method\": \"Hepatocyte-specific KLF10 KO, liver circadian transcriptome profiling, metabolic challenge assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — hepatocyte-specific KO with comprehensive transcriptome and in vivo metabolic phenotyping\",\n      \"pmids\": [\"34402428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KLF10 binds the IL-9 promoter and interacts with HDAC1 to inhibit IL-9 transcription in CD4+ T cells; KLF10 deficiency in T cells elevates IL-9, which activates fibroblast calcium mobilization and promotes perivascular fibrosis.\",\n      \"method\": \"ChIP (KLF10-IL-9 promoter, HDAC1 interaction), CD4-specific KO mouse, Ang II infusion model, anti-IL9 antibody rescue, scRNA-seq\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP with HDAC1 co-recruitment, in vivo KO with antibody rescue, scRNA-seq\",\n      \"pmids\": [\"35440172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KLF10 negatively regulates HO-1 gene transcription by directly binding to its promoter in vascular smooth muscle cells exposed to high glucose, thereby increasing ROS generation.\",\n      \"method\": \"ChIP, dual-luciferase reporter assay, KLF10 OE/KD, ROS measurement\",\n      \"journal\": \"Journal of ethnopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP with direct promoter binding and functional ROS assay, single lab\",\n      \"pmids\": [\"32738388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Exercise induces hepatic KLF10 expression through the cAMP/PKA/CREB pathway; KLF10 activates fumarate hydratase 1 (Fh1) expression, reducing fumarate accumulation and H3K4me3 marks on lipogenic gene promoters, thereby attenuating hepatocyte steatosis and NASH.\",\n      \"method\": \"Hepatocyte-specific KO and OE mice, treadmill exercise model, pathway inhibitors, Fh1 expression assay, H3K4me3 ChIP, NASH dietary model\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic chain from exercise stimulus to KLF10 → Fh1 → epigenetic marks, with hepatocyte-specific KO/OE validation\",\n      \"pmids\": [\"38615945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HPV-16 oncoprotein E7 physically interacts with KLF10 (TIEG1) by binding its C-terminus, promotes KLF10 ubiquitination and degradation via the proteasomal pathway, and attenuates KLF10-mediated apoptosis.\",\n      \"method\": \"Yeast two-hybrid, Co-immunoprecipitation, ubiquitination assay, apoptosis assay\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — yeast two-hybrid confirmed by Co-IP with functional degradation and apoptosis assays, single lab\",\n      \"pmids\": [\"20691807\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KLF10 (TIEG1) is a TGFβ-inducible Krüppel-like zinc finger transcription factor that binds GC-rich/Sp1 sites to repress or activate target gene promoters by recruiting chromatin-modifying corepressors (HDAC1, JARID1B/KDM5B, Sin3) or acting as a coactivator (with PCAF, Lef1/β-catenin); its activity and stability are post-translationally regulated by RAF-1-mediated phosphorylation at Thr93 (enabling PIN1 isomerase-dependent degradation), AMPK-mediated phosphorylation at Thr189 (stabilizing the protein), and Itch/Tyk2-mediated K27- and K63-linked ubiquitination (controlling nuclear localization and nonproteolytic enhancement of function); through these mechanisms KLF10 amplifies TGFβ/Smad signaling (by repressing Smad7 and activating Smad2), regulates immune cell differentiation (Foxp3, TGFβRII, IL-9, IL-12p40), bone homeostasis (Runx2, Osterix, RANKL/OPG, Wnt/β-catenin), circadian metabolic outputs (Bmal1, Pepck, Pgc-1α, SREBP-1C, zDHHC7/CD36), EMT (SLUG repression), and apoptosis (via ROS/mitochondrial pathway, Bcl-2 family, and BI-1).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KLF10 (TIEG1) is a TGFβ-inducible Krüppel-like zinc finger transcription factor that functions as a central integrator of TGFβ/BMP, Wnt, circadian, and metabolic signaling by binding GC-rich/Sp1 and GT-rich elements in target gene promoters to either repress or activate transcription [PMID:10506214, PMID:12804117]. KLF10 represses target genes (Smad7, SLUG, EGFR, Bmal1, SREBP-1C, IL-9, C/EBPα) by recruiting HDAC1 or the H3K4 demethylase JARID1B/KDM5B, and activates others (Foxp3, TGFβRII, Runx2, Osterix, Pgc-1α, zDHHC7) through association with PCAF acetyltransferase or Lef1/β-catenin, with the choice between repression and activation governed by an N-terminal Sin3-HDAC interaction domain whose inactivation switches KLF10 to an activating mode [PMID:24944246, PMID:22025675, PMID:20863814, PMID:28249899, PMID:19602726]. Protein stability and nuclear localization are controlled by opposing post-translational modifications: RAF-1 phosphorylation at Thr93 licenses PIN1-mediated degradation, AMPK phosphorylation at Thr189 stabilizes the protein, and Tyk2-mediated phosphorylation at Tyr179 triggers K27-linked ubiquitination that blocks nuclear entry, while Itch-mediated K63-linked ubiquitination enhances KLF10 transcriptional function [PMID:23994618, PMID:34869587, PMID:21471442, PMID:18278048]. Through these mechanisms, KLF10 controls TGFβ signal amplification, regulatory T cell differentiation, bone formation and remodeling, circadian hepatic metabolism and gluconeogenesis, adipogenesis, epithelial-mesenchymal transition, and apoptosis via the mitochondrial ROS/caspase pathway [PMID:20385766, PMID:33378664, PMID:15657444, PMID:34402428, PMID:10573529].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that KLF10 is not merely a TGFβ-responsive marker but a functional effector: overexpression was sufficient to induce apoptosis in TGFβ-sensitive epithelial cells, implicating KLF10 as a mediator of TGFβ growth-inhibitory signaling.\",\n      \"evidence\": \"Stable transfection and cell viability assays in PANC1 pancreatic cells\",\n      \"pmids\": [\"9153278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous loss-of-function not tested\", \"Mechanism of apoptosis induction unknown\", \"Generalizability to other cell types unclear\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defining the structural basis for KLF10 transcriptional repression and the apoptotic mechanism: three discrete N-terminal repression domains were mapped, and the apoptosis pathway was shown to proceed through ROS generation, mitochondrial depolarization, and caspase-3 activation.\",\n      \"evidence\": \"GAL4-based mutagenesis/reporter assays for repression domains; ROS, mitochondrial membrane potential, and caspase assays in Hep3B cells for apoptosis\",\n      \"pmids\": [\"10506214\", \"10573529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Corepressor partners for each repression domain unidentified\", \"Endogenous target genes mediating apoptosis unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defining the DNA-binding specificity of KLF10: SELEX identified a GT-rich core consensus (5'-GGTGTG-3'), establishing that KLF10 recognizes GC/GT-rich elements distinct from but overlapping with canonical Sp1 sites.\",\n      \"evidence\": \"Iterative nitrocellulose filter binding/SELEX with mutagenesis validation and VP16 transcriptional assay\",\n      \"pmids\": [\"12804117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide binding profile not determined\", \"Relationship between GT-rich and GC-rich site usage in vivo unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Loss-of-function evidence established KLF10 as essential for bone homeostasis: KLF10 KO osteoblasts failed to mineralize properly and showed altered RANKL/OPG ratio, while female KO mice developed osteopenia with reduced bone formation.\",\n      \"evidence\": \"TIEG1 knockout mouse with calvarial osteoblast culture, mineralization and co-culture assays; DXA, micro-CT, histomorphometry in congenic null mice\",\n      \"pmids\": [\"15657444\", \"18396127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Gender-specific mechanism unexplained\", \"Direct transcriptional targets mediating bone phenotype not yet mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"KLF10 was placed at the center of regulatory T cell biology through two discoveries: Itch-mediated K63-linked ubiquitination enhances KLF10 to induce Foxp3, while IL-6/Tyk2-mediated K27-linked ubiquitination blocks KLF10 nuclear entry—establishing opposing ubiquitin codes that toggle Treg versus effector fate.\",\n      \"evidence\": \"Co-IP, ubiquitin-linkage-specific assays, KO mouse airway inflammation (Itch/K63); phosphorylation mapping, nuclear translocation assays, KO tumor studies (Tyk2/K27)\",\n      \"pmids\": [\"18278048\", \"21471442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Deubiquitinase(s) reversing K63 or K27 chains unknown\", \"Whether both ubiquitin modifications occur on the same KLF10 molecule unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"KLF10 was shown to directly transactivate both TGFβ1 and Foxp3 promoters in CD4+ T cells, creating a positive feedback loop for TGFβ signaling; KLF10-deficient Tregs had impaired suppressor function rescuable by exogenous TGFβ1.\",\n      \"evidence\": \"KLF10 KO mouse, promoter transactivation assays, cytokine measurement, in vivo atherosclerosis model\",\n      \"pmids\": [\"19602726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin remodeling events at Foxp3 locus during KLF10 binding not characterized\", \"Relative contribution of KLF10 versus other KLFs in Treg function undefined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"KLF10 was integrated into the circadian clock hierarchy: CLOCK-BMAL1 drives circadian Klf10 expression via E-box elements, and KLF10 in turn represses Bmal1 transcription (forming a secondary feedback loop) and represses the gluconeogenic gene Pepck, linking the clock to hepatic glucose metabolism.\",\n      \"evidence\": \"ChIP for BMAL1 at Klf10 promoter, ChIP for KLF10 at Bmal1 GC boxes, KO mouse metabolic phenotyping, bioluminescence circadian assays\",\n      \"pmids\": [\"20385766\", \"20070857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of clock-controlled KLF10 target genes not mapped\", \"Whether KLF10 feeds back to CLOCK protein levels unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of corepressor partners for KLF10: JARID1B/KDM5B was shown to bind KLF10 repression domains and augment Smad7 repression, while HPV-16 E7 was found to target KLF10 for proteasomal degradation—revealing both physiological and pathological regulation of KLF10 repressor complexes.\",\n      \"evidence\": \"Co-IP and domain-binding assays for JARID1B; yeast two-hybrid and Co-IP with ubiquitination/degradation assays for E7\",\n      \"pmids\": [\"20863814\", \"20691807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether JARID1B and HDAC1 co-occupy the same KLF10-target promoters simultaneously untested\", \"HPV E7 interaction not validated by reciprocal endogenous Co-IP\", \"E7-KLF10 interaction not confirmed in HPV-infected primary cells\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"KLF10 was shown to directly regulate key osteogenic (Runx2) and oncogenic (EGFR) targets by recruiting distinct chromatin-modifying complexes: KLF10 co-activates Runx2 through direct promoter binding and protein interaction, while it represses EGFR by recruiting HDAC1 to Sp1 sites, suppressing breast cancer metastasis.\",\n      \"evidence\": \"ChIP, Co-IP, domain mutagenesis, KO osteoblast rescue for Runx2; ChIP, Co-IP of KLF10-HDAC1, xenograft model for EGFR\",\n      \"pmids\": [\"21559363\", \"22025675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KLF10-Runx2 protein interaction is direct or bridged unknown\", \"Full spectrum of HDAC1-dependent KLF10 target genes in breast cancer not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Post-translational control of KLF10 stability was elucidated: RAF-1 phosphorylates KLF10 at Thr93, which creates a binding motif for PIN1 prolyl isomerase, promoting KLF10 degradation—linking RAS-RAF signaling to TGFβ pathway attenuation.\",\n      \"evidence\": \"In vitro kinase assay, site-directed mutagenesis, yeast two-hybrid and Co-IP for PIN1, cycloheximide chase\",\n      \"pmids\": [\"23994618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating PIN1-dependent degradation not identified\", \"Whether other MAPK pathway kinases phosphorylate Thr93 untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The dual-mode chromatin switch mechanism of KLF10 was defined: an intact N-terminal Sin3-HDAC domain enforces repression of Foxp3, but when this domain is inactivated, KLF10 associates with PCAF acetyltransferase to activate Foxp3—explaining how a single transcription factor toggles between repression and activation at the same locus.\",\n      \"evidence\": \"ChIP, genome-integrated reporter assays, domain deletion/mutation, primary lymphocyte assays\",\n      \"pmids\": [\"24944246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal that inactivates the Sin3-HDAC domain in vivo not identified\", \"Whether this toggle mechanism applies to non-immune targets unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"KLF10 was established as a master regulator of TGFβ receptor expression in immune cells: direct binding to the TGFβRII promoter enhances receptor levels and Smad2 phosphorylation in both CD8+ T cells and macrophages, with KLF10 deficiency producing pro-inflammatory phenotypes.\",\n      \"evidence\": \"ChIP in CD8+ T cells and macrophages, KLF10 KO mouse with flow cytometry and cytokine ELISA, in vivo viral infection and bone marrow transfer\",\n      \"pmids\": [\"25472963\", \"26472224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KLF10 also regulates TGFβRI expression untested\", \"Mechanism of histone H3 acetylation increase at TGFβRII promoter (which acetyltransferase?) unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multiple parallel advances established KLF10 as an anti-EMT factor (repressing SLUG via HDAC1 recruitment), a Wnt pathway co-activator (interacting with Lef1/β-catenin in bone), a metabolic regulator (activating Pgc-1α for gluconeogenesis), and an amplifier of TGFβ signaling (repressing Smad7 at a defined GC-box).\",\n      \"evidence\": \"ChIP with HDAC1 co-recruitment and EMT metrics for SLUG; Co-IP with Lef1/β-catenin and Wnt reporter for Wnt; ChIP and adenoviral OE/KD in mice for Pgc-1α; ChIP with defined binding site mutagenesis for Smad7\",\n      \"pmids\": [\"28249899\", \"28201653\", \"28836014\", \"28108300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SLUG repression and Smad7 repression use the same HDAC1 complex unclear\", \"Wnt co-activator function not tested outside osteoblast context\", \"Relative importance of Pgc-1α versus Pepck repression for gluconeogenic output not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"KLF10 was positioned in the adipogenic transcriptional cascade: C/EBPβ induces KLF10 early in adipogenesis, and KLF10 then recruits HDAC1 to repress C/EBPα and PPARγ, establishing a temporal brake on differentiation.\",\n      \"evidence\": \"ChIP for C/EBPβ at KLF10 promoter and KLF10/HDAC1 at C/EBPα promoter, promoter deletion analysis, 3T3-L1 differentiation assay\",\n      \"pmids\": [\"30026232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KLF10 also regulates later stages of adipogenesis unknown\", \"In vivo adipose-specific KO phenotype not reported\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Cell-specific KO demonstrated that T cell-intrinsic KLF10 controls systemic metabolism: CD4-specific KLF10 deletion caused obesity, insulin resistance, and fatty liver through impaired Treg mobilization linked to reduced mitochondrial respiration and PI3K-Akt-mTOR signaling, fully rescued by WT Treg transfer.\",\n      \"evidence\": \"CD4-specific KO mouse, adoptive transfer rescue, metabolic phenotyping, mitochondrial respiration assay\",\n      \"pmids\": [\"33378664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct KLF10 transcriptional targets controlling Treg metabolism not identified\", \"Whether KLF10 in other immune subsets contributes to metabolic phenotype untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Two stabilizing/destabilizing post-translational pathways and a new lipogenic mechanism were defined: AMPK phosphorylation at Thr189 stabilizes KLF10 to repress SREBP-1C and suppress lipogenesis, while KLF10 also activates zDHHC7 transcription to drive CD36 palmitoylation and hepatic lipid uptake in NASH; hepatocyte-specific KO confirmed KLF10 integrates circadian and sugar signals for energy metabolism.\",\n      \"evidence\": \"In vitro kinase assay with Thr189 mutagenesis, ChIP-chip, hepatocyte-specific KO NAFLD model for AMPK/SREBP-1C; transcriptomics, palmitoylation assay, diet-induced NASH model for zDHHC7/CD36; hepatocyte-specific KO circadian transcriptome for circadian integration\",\n      \"pmids\": [\"34869587\", \"35492028\", \"34402428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How AMPK-stabilized KLF10 represses SREBP-1C while also activating zDHHC7 (seemingly pro-lipogenic) is paradoxical and unresolved\", \"Whether circadian KLF10 oscillation modulates AMPK phosphorylation unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"KLF10 was identified as a direct repressor of IL-9 in CD4+ T cells via HDAC1 recruitment, with KLF10 deficiency driving IL-9-dependent perivascular fibrosis; separately, KLF10 represses HO-1 in vascular smooth muscle cells under high glucose.\",\n      \"evidence\": \"ChIP for KLF10 and HDAC1 at IL-9 promoter, CD4-specific KO with Ang II model and anti-IL-9 rescue, scRNA-seq; ChIP and reporter assay with ROS measurement for HO-1\",\n      \"pmids\": [\"35440172\", \"32738388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL-9 repression uses the same Sin3-HDAC complex as other targets unclear\", \"In vivo relevance of HO-1 repression to diabetic vascular disease not confirmed in KO models\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Exercise-induced KLF10 expression was traced through a cAMP/PKA/CREB pathway to activation of fumarate hydratase 1 (Fh1), which reduces fumarate and H3K4me3 at lipogenic gene promoters, providing a mechanistic link between physical activity and NASH attenuation.\",\n      \"evidence\": \"Hepatocyte-specific KO and OE mice, treadmill exercise model, pathway inhibitors, Fh1 expression assay, H3K4me3 ChIP, NASH dietary model\",\n      \"pmids\": [\"38615945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the Fh1-fumarate-H3K4me3 axis is the dominant mechanism or one of several remains unclear\", \"Long-term exercise studies in KLF10 KO not performed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Several key mechanistic questions remain: (1) genome-wide binding maps in primary tissues have not been reported, (2) the structural basis for the Sin3-HDAC versus PCAF coactivator switch is undefined, (3) how RAF-1/PIN1-mediated degradation versus AMPK-mediated stabilization are coordinated in real time is unknown, and (4) whether KLF10 PTM codes (phosphorylation, K27/K63-ubiquitination) are integrated combinatorially to control nuclear access and target selection has not been tested.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No genome-wide ChIP-seq or CUT&RUN in primary cells published\", \"Structural model of KLF10-corepressor/coactivator toggle unavailable\", \"Combinatorial PTM code logic untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 14, 17, 18, 20, 22, 30, 31, 32, 40]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 5, 12, 14, 18, 20, 24, 29, 30, 31, 35, 40, 42]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16, 17, 24, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": [2, 5, 12, 14, 18, 24, 29, 30, 31, 35, 40, 42]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 12, 16, 25, 26, 31, 33]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1, 5, 8]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [13, 32, 39, 40, 41, 44]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 12, 16, 20, 25, 26, 38, 42]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [13, 14, 41]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [15, 24, 35, 44]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 11, 17, 29, 33]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"HDAC1\",\n      \"KDM5B\",\n      \"PCAF\",\n      \"PIN1\",\n      \"ITCH\",\n      \"CTNNB1\",\n      \"LEF1\",\n      \"RUNX2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}