{"gene":"SETD7","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2002,"finding":"Set9 (SETD7) was isolated from human cells and shown to specifically monomethylate lysine 4 of histone H3 (H3-K4). This methylation precludes association of the NuRD histone deacetylase complex with the H3 tail, and also impairs Suv39h1-mediated methylation at H3-K9, thereby promoting transcription activation.","method":"Biochemical isolation, in vitro histone methyltransferase assay, histone tail binding assay, cross-inhibition assay with Suv39h1 and G9a","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with multiple orthogonal biochemical assays; foundational paper replicated by subsequent studies","pmids":["11850410"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of a ternary complex of human SET7/9 with a histone H3 peptide and cofactor (AdoMet) revealed that the peptide substrate and cofactor bind on opposite surfaces of the enzyme, the target lysine inserts its side chain into a narrow channel connecting the two surfaces, and SET7/9 is exclusively a mono-methylase due to active-site geometry.","method":"High-resolution X-ray crystallography of ternary complex; solution studies confirming mono-methylase activity","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of ternary complex with functional validation; landmark structural study","pmids":["12540855"],"is_preprint":false},{"year":2004,"finding":"SET9 (SETD7) monomethylates the TBP-associated factor TAF10 at a single lysine in its histone-fold domain (loop 2 region), and this methylation increases TAF10 affinity for RNA polymerase II, potentiating transcription of a subset of TAF10-dependent genes in a promoter-specific manner.","method":"In vitro methyltransferase assay, affinity pull-down, reporter assays, TAF10-null cell complementation with methylation-deficient mutant","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro methylation assay plus mutagenesis plus cell-based rescue; multiple orthogonal methods in one study","pmids":["15099517"],"is_preprint":false},{"year":2006,"finding":"Crystal structures of SET7/9 bound to TAF10 and other substrate peptides revealed that the enzyme recognizes a conserved K/R-S/T/A motif preceding the target lysine, and has preference for aspartates/asparagines C-terminal to the target lysine, defining the substrate-specificity consensus motif. TAF7 was identified as a novel substrate (methylated at Lys5 in vitro) using this motif.","method":"X-ray crystallography, substrate peptide mutagenesis, in vitro methyltransferase assays with multiple substrates","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures plus mutagenesis plus in vitro assays across multiple substrates","pmids":["16415881"],"is_preprint":false},{"year":2007,"finding":"QM/MM molecular dynamics simulations of SET7/9 identified Tyr-335 as the general base for deprotonation of the methylated lysine after AdoHcy dissociation, and showed that conformational changes bring Y335 to the target lysine for proton abstraction, explaining mono-methylase product specificity. Y305F and Y335F mutants were analyzed to support the mechanism.","method":"Quantum mechanical/molecular mechanical (QM/MM) molecular dynamics and free-energy simulations; mutant analysis (Y305F, Y335F)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1 (computational with mutant analysis) / Moderate — rigorous simulations with experimental mutant correlation but primarily computational","pmids":["17517655"],"is_preprint":false},{"year":2008,"finding":"SETD7 directly methylates estrogen receptor alpha (ERα) at lysine 302. SET7-mediated K302 methylation stabilizes ERα protein and is required for efficient recruitment of ERα to its target gene promoters and their transactivation. A breast cancer-associated mutation K303R alters K302 methylation in vitro and in vivo. Crystal structure of the SET7-ER peptide complex revealed the molecular basis of recognition.","method":"In vitro methyltransferase assay, X-ray crystallography of SET7-ER peptide complex, Co-IP, ChIP, mutagenesis, K303R cancer mutation analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro methylation plus mutagenesis plus chromatin recruitment assays in one study","pmids":["18471979"],"is_preprint":false},{"year":2008,"finding":"SET7/9 acts as a novel coactivator of NF-κB. SET7/9 knockdown in monocytes inhibits TNF-α-induced H3K4 methylation at NF-κB target gene promoters, reduces NF-κB p65 recruitment to those promoters, and attenuates inflammatory gene expression and monocyte adhesion.","method":"siRNA knockdown, ChIP, gene expression analysis (microarray), monocyte adhesion assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional KD assays in multiple contexts, single lab","pmids":["18650421"],"is_preprint":false},{"year":2008,"finding":"Set7/9 methylates p53 at K369 (mouse)/K372 (human) in vivo. Cells from Set7/9 knockout mice fail to methylate p53 K369, cannot induce p53 downstream targets upon DNA damage, and are predisposed to oncogenic transformation. Mechanistically, Set7/9-mediated p53 methylation is required for binding of the acetyltransferase Tip60 to p53 and for subsequent p53 acetylation.","method":"Set7/9 knockout mouse generation, MEF-based DNA damage assays, Co-IP (Tip60-p53), p53 acetylation analysis, transformation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic knockout mouse model with multiple orthogonal functional readouts and mechanistic Co-IP","pmids":["18280244"],"is_preprint":false},{"year":2009,"finding":"SET7 directly interacts with DNMT1, colocalizes with it, and specifically monomethylates DNMT1 at Lys-142. This methylation promotes proteasome-mediated DNMT1 degradation, peaking during S and G2 phases. SET7 overexpression decreases DNMT1 levels; SET7 siRNA knockdown stabilizes DNMT1.","method":"Co-IP, colocalization (immunofluorescence), in vitro methyltransferase assay, proteasome inhibitor experiments, siRNA KD, SET7 overexpression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct interaction confirmed by Co-IP and pulldown, in vitro methylation assay, gain- and loss-of-function experiments","pmids":["19282482"],"is_preprint":false},{"year":2009,"finding":"Set9 (SETD7) physically associates with the RelA subunit of NF-κB and monomethylates RelA at lysine residues 314 and 315 in vitro and in vivo. This methylation inhibits NF-κB action by inducing proteasome-mediated degradation of promoter-associated RelA, limiting the duration of NF-κB target gene expression.","method":"Co-IP, in vitro methyltransferase assay, mutational analysis, mass spectrometry, siRNA KD, reporter assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mass spectrometry identification of methylation sites, in vitro assay, mutagenesis, and cellular functional validation","pmids":["19262565"],"is_preprint":false},{"year":2010,"finding":"Set7/9 (KMT7) monomethylates lysine 51 in the RNA-binding domain of HIV-1 Tat. Set7/9 associates with the HIV promoter in vivo, binds TAR RNA by itself and in complex with Tat and P-TEFb. Knockdown of Set7/9 suppresses Tat transactivation in a methylation-dependent manner (K51A Tat is refractory to Set7/9 KD).","method":"In vitro methyltransferase assay, ChIP, RNA binding assay (TAR RNA), siRNA KD, luciferase reporter assay with K51A mutant","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro methylation, RNA binding, ChIP, and genetic validation with methylation-deficient mutant in one study","pmids":["20227666"],"is_preprint":false},{"year":2010,"finding":"SETD7 directly methylates and regulates the androgen receptor (AR). SET9 methylates AR at lysine 632 (also reported as K630 in a parallel study), which is necessary for enhancing AR transcriptional activity by facilitating inter-domain N-C communication and recruitment to androgen-target gene promoters.","method":"In vitro methyltransferase assay, Co-IP, ChIP, mutagenesis (K632A), N-C interaction assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct methylation demonstrated in vitro and in vivo with mutagenesis and functional ChIP assays; replicated by independent lab (PMID:21273441)","pmids":["20959290","21273441"],"is_preprint":false},{"year":2011,"finding":"Set7/9 interacts with SIRT1 both in vitro and in vivo. Upon DNA damage, Set7/9-SIRT1 interaction is enhanced, suppressing SIRT1-p53 interaction and abrogating SIRT1-mediated p53 deacetylation, thereby promoting p53-mediated transactivation. This regulation operates in addition to direct p53 methylation.","method":"Co-IP (in vitro and in vivo), p53 acetylation analysis, SIRT1 methylation analysis, reporter assays, DNA damage response assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional assays in single lab","pmids":["21245319"],"is_preprint":false},{"year":2011,"finding":"Two independent Set7/9 knockout mouse strains showed that Set7/9 is dispensable for p53-dependent cell cycle arrest, apoptosis, and p53 acetylation following DNA damage or oncogene activation in vivo, contradicting the earlier finding (PMID:18280244) that p53 methylation by Set7/9 is required for p53 activation.","method":"Independent Set7/9 knockout mouse strain, DNA damage assays (irradiation, genotoxic agents), p53 target gene expression, p53 acetylation analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent knockout mouse strains (PMIDs 21855806 and 21855805) with comprehensive in vivo phenotypic analysis yielding negative results","pmids":["21855806","21855805"],"is_preprint":false},{"year":2011,"finding":"Set7 directly interacts with MyoD and promotes skeletal muscle differentiation. Set7 knockdown or dominant-negative expression impairs myoblast differentiation with decreased H3K4me1, reduced expression of myocyte enhancer factor 2 and contractile proteins, and myofibril assembly defects. Set7 activates muscle genes by precluding Suv39h1-mediated H3K9 methylation on myogenic gene promoters.","method":"Co-IP (Set7-MyoD), siRNA KD, dominant-negative overexpression, ChIP (H3K4me1, H3K9me), differentiation assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, KD functional phenotype; single lab","pmids":["21859860"],"is_preprint":false},{"year":2011,"finding":"Set9 directly methylates FoxO3 at lysine 271 (identified by tandem mass spectrometry and methyl-specific antibody). Set9-mediated FoxO3 methylation decreases FoxO3 protein stability while moderately increasing its transcriptional activity.","method":"In vitro methyltransferase assay, tandem mass spectrometry, methyl-specific antibody, protein stability assay","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro methylation confirmed by MS and methyl-specific antibody, functional stability assay; single lab","pmids":["22820736"],"is_preprint":false},{"year":2011,"finding":"SET7/9 can methylate multiple new peptide substrates from human proteins. Confirmed methylation of nine nonhistone proteins (AKA6, CENPC1, MeCP2, MINT, PPARBP, ZDH8, Cullin1, IRF1, TTK) and H2A and H2B in vitro and in vivo. Phosphorylation of substrate proteins adjacent to the target lysine inhibits SET7/9 methylation. MINT protein can be dimethylated by SET7/9 showing context-dependent product specificity.","method":"Peptide array methylation, in vitro methyltransferase assays with protein domains, in vivo methylation validation with antibodies","journal":"Chemistry & biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — systematic peptide array and in vitro/in vivo protein methylation confirmed for multiple substrates; single lab","pmids":["21276944"],"is_preprint":false},{"year":2012,"finding":"Set7 (Setd7) monomethylates YAP at lysine 494. This methylation is critical for cytoplasmic retention of YAP. Set7 knockout mice have a larger intestinal progenitor compartment with increased YAP target gene expression, placing Set7-mediated YAP methylation as a regulatory checkpoint in the Hippo pathway.","method":"Set7 knockout mouse model, intestinal progenitor analysis, in vitro methyltransferase assay, YAP subcellular localization studies, YAP target gene expression","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse genetics combined with mechanistic in vitro methylation and subcellular localization studies; replicated by subsequent work (PMID:27046831, 35709329)","pmids":["23850191"],"is_preprint":false},{"year":2012,"finding":"SET7/9 directly methylates SUV39H1 at lysines 105 and 123 (identified by mass spectrometry and methyl-specific antibodies). Methylation dramatically down-regulates SUV39H1 methyltransferase activity, leading to decreased H3K9 trimethylation in heterochromatin, heterochromatin relaxation (increased Sat2 and α-Sat expression), and genome instability in response to DNA damage.","method":"Co-IP, GST pulldown, in vitro methyltransferase assay, mass spectrometry, methyl-specific antibody, micrococcal nuclease sensitivity assay, immunofluorescence","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mass spectrometry identification of methylation sites, in vitro and in vivo validation, mechanistic functional readout; multiple orthogonal methods","pmids":["23509280"],"is_preprint":false},{"year":2012,"finding":"SET7/9 directly methylates the farnesoid X receptor (FXR) at lysine 206 in vivo and in vitro. Methylation enhances FXR/RXRα binding to the FXRE and potentiates transactivation of FXR target genes (SHP, BSEP). Methylation-deficient K206R mutant FXR shows impaired transactivation; SET7/9 methyltransferase-dead mutant is also inactive.","method":"In vitro methyltransferase assay, Co-IP, GST pulldown, mammalian two-hybrid, EMSA, luciferase reporter assay, K206R mutagenesis, siRNA KD","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including in vitro methylation, EMSA, mutagenesis, and reporter assays in one study","pmids":["22345554"],"is_preprint":false},{"year":2012,"finding":"SET7/9 methylates histone H1.4 at multiple lysine residues (K121, K129, K159, K171, K177, K192) in KAK motifs of the C-terminal domain. ADP-ribosylation of H3 by ARTD1 prevents H3 methylation by SET7/9 but allows subsequent SET7/9 methylation of H1. H1 and H3 compete for SET7/9-dependent methylation, revealing substrate competition as a regulatory mechanism.","method":"In vitro methyltransferase assay with isolated histones, mass spectrometry identification of methylation sites, competition assays","journal":"Epigenetics & chromatin","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro assays with mass spectrometry site identification; single lab, mechanistic follow-up limited","pmids":["23289424"],"is_preprint":false},{"year":2013,"finding":"SET7/9 directly methylates ARTD1 (PARP1) at K508 in vitro and in vivo. ARTD1 methylation by SET7/9 enhances poly-ADP-ribose (PAR) synthesis upon oxidative stress in vivo, and promotes ARTD1 recruitment to sites of laser-induced DNA damage in a SET7/9-dependent manner. ARTD1 auto-modification inhibits its methylation by SET7/9.","method":"In vitro methyltransferase assay, in vivo methylation detection, laser irradiation/PAR formation assay, live-cell imaging of ARTD1 recruitment","journal":"Open biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro methylation plus in vivo functional readout; single lab","pmids":["24088713"],"is_preprint":false},{"year":2013,"finding":"Negative regulation of TGF-β signaling: Set9 methylates Smad7 (an inhibitory TGF-β effector), promoting Smad7 interaction with the E3 ligase Arkadia and subsequent ubiquitination-dependent degradation of Smad7. Set9 depletion or pharmacological inhibition elevates Smad7 levels and inhibits TGF-β-dependent extracellular matrix gene expression. Set9-deficient mice show severely compromised lung fibrosis.","method":"In vitro methyltransferase assay, Co-IP (Smad7-Arkadia), ubiquitination assay, Set9 KO mouse model of pulmonary fibrosis (bleomycin/Ad-TGF-β), siRNA and pharmacological inhibitor studies","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro methylation, Co-IP, ubiquitination assay, in vivo mouse model; multiple orthogonal methods","pmids":["27292644"],"is_preprint":false},{"year":2014,"finding":"(R)-PFI-2 was identified as a potent (Ki = 0.33 nM), selective, cofactor-dependent, substrate-competitive inhibitor of SETD7. Crystal structure showed it occupies the substrate peptide binding groove including the lysine-binding channel and contacts the methyl group of SAM. In murine embryonic fibroblasts, (R)-PFI-2 phenocopied Setd7 deficiency on Hippo pathway signaling via YAP modulation; in confluent MCF7 cells it rapidly altered YAP localization.","method":"Biochemical inhibitor characterization (Ki determination), X-ray crystallography, chemoproteomics (biotinylated probe competition), cell-based YAP localization assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, biochemical Ki, chemoproteomics, and cell-based phenocopy of genetic KO in one study","pmids":["25136132"],"is_preprint":false},{"year":2014,"finding":"Set7/9 physically interacts with Mdm2 and regulates expression of Mdm2 at the transcriptional level, affecting the DNA damage response. Multiple cancer cell lines with inverse expression of Set7/9 and Mdm2 show diminished survival in response to genotoxic stress.","method":"Co-IP, gene expression analysis, cell viability assays under genotoxic stress, bioinformatics","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and expression correlation; limited mechanistic depth in abstract","pmids":["26317544"],"is_preprint":false},{"year":2014,"finding":"Set7/9 is a critical co-activator of E2F1-dependent transcription in response to DNA damage. Set7/9 indirectly modulates histone modifications at E2F1-dependent gene promoters, promotes CCNE1 expression (proliferation), and represses TP73 gene expression (anti-apoptotic). Cell cycle progression through G1/S checkpoint depends on threshold expression of both E2F1 and Set7/9.","method":"Co-IP, ChIP, gene expression analysis, cell biology assays (G1/S progression), bioinformatics across lung tumor cell lines","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-based histone modification analysis plus functional cell cycle assays; single lab","pmids":["25124555"],"is_preprint":false},{"year":2015,"finding":"Set7 methylates HIF-1α at lysine 32 and HIF-2α at lysine K29, inhibiting HIF-α transcriptional activity by impairing occupancy of HIF-α on hypoxia response elements of target gene promoters. Set7-null fibroblasts and Set7 KD/inhibited cells show upregulated HIF target genes and increased glucose uptake.","method":"In vitro methyltransferase assay, ChIP (HIF-α at HRE), Set7 KO fibroblasts, shRNA KD, Set7 inhibitor treatment, glucose uptake assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro methylation plus ChIP plus KO/KD functional phenotype; single lab","pmids":["25897119"],"is_preprint":false},{"year":2015,"finding":"Set7 monomethylates Gli3 full-length (but not truncated form) at K436 and K595. Methylation at K436 increases Gli3 stability and methylation at K595 increases Gli3 DNA binding ability, together enhancing Shh signaling activation and contributing to tumor growth/metastasis in non-small cell lung cancer.","method":"In vitro methyltransferase assay, mutagenesis (K436A, K595A), protein stability assay, DNA binding assay, Shh target gene expression, in vitro/in vivo tumor assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro methylation with mutagenesis and functional stability/DNA binding readouts; single lab","pmids":["27146893"],"is_preprint":false},{"year":2015,"finding":"Set7/9 methylates the transcription factor Pdx1 at K123 and K131 (identified by mass spectrometry and mutagenesis of purified proteins). K131 methylation (but not K123) is required for transcriptional augmentation by Set7/9. Conditional deletion of Set7/9 in β cells causes glucose intolerance and impaired glucose-stimulated insulin secretion with reduced Pdx1 target gene expression.","method":"In vitro methyltransferase assay, mass spectrometry, mutagenesis, luciferase reporter assay, conditional knockout mouse (Set(Δ)β), islet glucose-stimulated insulin secretion assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — MS-identified methylation sites, mutagenesis, in vivo conditional KO with defined metabolic phenotype; multiple orthogonal methods","pmids":["25713082"],"is_preprint":false},{"year":2015,"finding":"SET7/9 directly methylates β-catenin at lysine 180 (identified by mutagenesis and mass spectrometry). Methylated β-catenin is recognized by GSK-3β for degradation. K180R mutant β-catenin has a longer half-life. SET7/9 depletion or K180R mutation enhances Wnt/β-catenin target gene expression and promotes cancer cell growth.","method":"Co-IP, in vitro methyltransferase assay, mutagenesis (K180R), mass spectrometry, protein half-life assay, luciferase reporter assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro methylation, MS site identification, mutagenesis, functional stability assay, and cellular gene expression; multiple orthogonal methods","pmids":["26116705"],"is_preprint":false},{"year":2016,"finding":"SETD7-mediated methylation of YAP (K494) facilitates Wnt-induced nuclear accumulation of β-catenin. SETD7 is part of a complex containing YAP, AXIN1, and β-catenin. SETD7 is required for Wnt-driven intestinal tumorigenesis and regeneration, linking the Wnt/β-catenin and Hippo/YAP pathways.","method":"SETD7 KO mouse model (intestinal tumorigenesis/regeneration), Co-IP complex analysis (YAP-AXIN1-β-catenin-SETD7), β-catenin nuclear localization assay","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse tumor/regeneration model, complex Co-IP, mechanistic nuclear localization assays; builds on prior mechanistic work","pmids":["27046831"],"is_preprint":false},{"year":2016,"finding":"SET7/9 methylates transcription factor YY1 at two lysine residues, K173 and K411. This methylation regulates YY1 DNA-binding activity in vitro and at specific genomic loci in cells, affecting YY1-regulated gene transcription and cell proliferation.","method":"In vitro methyltransferase assay, mutagenesis, EMSA (DNA binding), ChIP, luciferase reporter assay, cell proliferation assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro methylation, mutagenesis, EMSA, and ChIP; single lab","pmids":["26902152"],"is_preprint":false},{"year":2018,"finding":"SETD7 controls cardiac differentiation by reading H3K36 marks independently of its enzymatic activity. During mesodermal formation, SETD7 associates with SWI/SNF chromatin-remodeling factors; in cardiac progenitors it associates with NKX2.5. SETD7 binds methylated H3K36 in gene bodies of target genes to facilitate RNA Pol II-dependent transcription.","method":"ChIP-seq, Co-IP (SETD7 with SWI/SNF and NKX2.5), enzymatic activity mutant analysis, H3K36me binding assay, differentiation assays from hPSCs","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genome-wide ChIP-seq, Co-IP with multiple co-factors, enzymatic-dead mutant used to separate reading from writing function; multiple orthogonal methods","pmids":["29499155"],"is_preprint":false},{"year":2018,"finding":"SET7 methylates SOX2 at K119 (mouse)/K117 (human) and K42, triggering ubiquitin-dependent SOX2 proteolysis. LSD1 demethylase removes methyl groups from both sites preventing degradation, while PHF20L1 binds monomethylated K42 and K117 to protect SOX2 from proteolysis. SET7/LSD1/PHF20L1 dynamically regulate SOX2 stability in pluripotent stem cells.","method":"In vitro methyltransferase assay, methylation-specific antibody, Co-IP, siRNA KD (LSD1, PHF20L1), protein stability assay, SET7 inactivation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro methylation plus stability assays plus KD of reader/eraser; single lab","pmids":["29358331"],"is_preprint":false},{"year":2018,"finding":"Rpl29 lysine 5 (Rpl29K5) is methylated exclusively by Set7/9 and can be demethylated by Lsd1. Rpl29 methylation has no effect on global protein synthesis but affects Rpl29 subcellular localization. Rpl29K5 methylation was validated as a specific cellular biomarker for Set7/9 activity, responsive to (R)-PFI-2 inhibitor treatment.","method":"In vitro methyltransferase assay (substrate identification), methylation-specific antibody, subcellular fractionation, Set7/9 inhibitor treatment, global translation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro methylation, specific antibody validation, cellular inhibitor response; single lab","pmids":["29959229"],"is_preprint":false},{"year":2019,"finding":"UHRF1 is methylated by SET7 and demethylated by LSD1. UHRF1 phosphorylation in S phase is a prerequisite for its interaction with SET7. SET7-mediated UHRF1 methylation catalyzes polyubiquitin chain conjugation to PCNA and promotes homologous recombination for DNA double-strand break repair. UHRF1 methylation is induced in response to DNA damage.","method":"In vitro methyltransferase assay, Co-IP, phosphorylation mutant analysis, polyubiquitination assay (PCNA), homologous recombination assay, cell viability assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro methylation, Co-IP, functional PCNA ubiquitination and HR assays; single lab","pmids":["30357346"],"is_preprint":false},{"year":2019,"finding":"SUMO-specific isopeptidase SENP3 associates with SETD7 and deSUMOylates it. By recruiting SETD7 to the MyHC-II gene locus, SENP3 promotes SETD7 association with active RNA polymerase II and precludes opposing Suv39h1 activity. SENP3 is degraded in cachexia, impairing this SENP3-SETD7 regulatory axis, resulting in disrupted MyHC-II expression and disorganized sarcomeres.","method":"Co-IP (SENP3-SETD7), deSUMOylation assay, ChIP (SETD7 and Pol II at MyHC-II), SENP3 KD functional assay, cachexia model","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, biochemical deSUMOylation, and ChIP-based mechanism; single lab","pmids":["31141694"],"is_preprint":false},{"year":2020,"finding":"SETD7 methylates PLK1 at K191 (dimethylation), tuning down PLK1 kinase activity by limiting ATP utilization at kinetochores during early mitosis. Non-methylatable PLK1 K191 mutant or chemical inhibition of SETD7 causes mitotic arrest due to destabilized kinetochore-microtubule attachments, revealing that SETD7-mediated PLK1 methylation promotes dynamic kinetochore-microtubule attachments for accurate error correction.","method":"In vitro methyltransferase assay, mutagenesis (K191), PLK1 kinase activity assay, kinetochore-microtubule attachment assay, SETD7 inhibitor treatment, mitosis assay","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro methylation, mutagenesis, kinase activity assay, and cell biology phenotype; single lab","pmids":["31863092"],"is_preprint":false},{"year":2021,"finding":"SETD7 methylates Tau at K132, an event that facilitates subsequent methylation at K130. Methylated Tau (identified by mass spectrometry in human AD brain) preferentially localizes to cell soma and nuclear fractions (absent from neurites) in hiPSC-derived neurons and mouse brain, and methylated Tau levels increase with Tau pathology stage.","method":"Mass spectrometry (human AD brain), methylation-specific antibody development, knockdown and inhibitor studies, subcellular fractionation, proteomics","journal":"Molecular neurodegeneration","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — MS identification in human tissue, specific antibody, KD/inhibitor validation, subcellular localization; single lab","pmids":["34215303"],"is_preprint":false},{"year":2023,"finding":"SETD7 methylates the Hippo pathway effector YAP upon energy deprivation in cardiomyocytes, leading to YAP cytosolic retention and impaired transcription of antioxidant genes MnSOD and CAT. This impairment causes mitochondrial ROS accumulation, organelle swelling, and apoptosis. Pharmacological inhibition of SETD7 by (R)-PFI-2 restores YAP nuclear localization and prevents myocardial ischemia/reperfusion injury in mice.","method":"NRVM culture (energy deprivation), SETD7 KO mouse I/R injury model, (R)-PFI-2 pharmacological inhibition, YAP localization assay, MnSOD/CAT expression, mtROS measurement, LV function assay","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo genetic/pharmacological approaches with mechanistic YAP localization and antioxidant gene expression readouts; translational human tissue validation","pmids":["35709329"],"is_preprint":false},{"year":2016,"finding":"TRIM21 physically associates with SETD7 and functions as a major negative regulator upstream of SETD7 through a proteasome-dependent ubiquitination mechanism, leading to SETD7 degradation. SETD7 promotes breast cancer malignant processes via activation of RUNX2.","method":"Mass spectrometry, Co-IP, GST pulldown, ubiquitination assay, ChIP-seq, ChIP, cell functional assays, xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, GST pulldown, and ubiquitination assay for TRIM21-SETD7 interaction/degradation; single lab","pmids":["32102992"],"is_preprint":false}],"current_model":"SETD7 (SET7/9, KMT7) is a SET-domain lysine methyltransferase that acts exclusively as a mono-methylase (established by crystal structure): it methylates histone H3K4 to promote transcription by blocking NuRD deacetylase binding and Suv39h1-mediated H3K9 methylation, and it methylates a broad array of non-histone substrates—including p53, ERα, DNMT1, NF-κB RelA, AR, TAF10, YAP, β-catenin, PLK1, FXR, Pdx1, SIRT1, SUV39H1, Smad7, Tat, HIF-1α/2α, FoxO3, Gli3, SOX2, ARTD1, UHRF1, YY1, and Tau—with each methylation event regulating the substrate's stability, activity, protein–protein interactions, or subcellular localization; its own activity is controlled by SENP3-mediated deSUMOylation and TRIM21-mediated proteasomal degradation, and it additionally reads H3K36 methylation marks (independently of catalysis) to drive stage-specific transcription during cardiac differentiation."},"narrative":{"mechanistic_narrative":"SETD7 (SET7/9, KMT7) is a SET-domain protein lysine methyltransferase that controls transcription and signaling by depositing a single methyl mark on histone and, predominantly, non-histone substrates [PMID:11850410, PMID:12540855]. Active-site geometry restricts it to mono-methylation: a target lysine inserts into a narrow channel between the substrate and AdoMet binding surfaces, and Tyr-335 acts as the catalytic base that limits product to the mono-methyl state [PMID:12540855, PMID:17517655]. Substrate selection follows a defined K/R-S/T/A consensus preceding the target lysine, and methylation is suppressed when adjacent residues are phosphorylated or otherwise modified [PMID:16415881, PMID:21276944]. On chromatin, SETD7 monomethylates histone H3K4 to activate transcription by excluding the NuRD deacetylase complex and antagonizing Suv39h1-mediated H3K9 methylation [PMID:11850410], a writer logic it reuses at myogenic promoters through direct interaction with MyoD [PMID:21859860]. The dominant biology of SETD7, however, is the methylation of transcription factors and signaling proteins, where individual marks tune substrate stability, DNA binding, partner recruitment, or subcellular localization: it methylates ERα, AR, FXR, Pdx1, and Gli3 to enhance their promoter recruitment and transactivation [PMID:18471979, PMID:20959290, PMID:21273441, PMID:22345554, PMID:25713082, PMID:27146893], while methylation of DNMT1, NF-κB RelA, β-catenin, FoxO3, and SOX2 directs them toward proteasomal degradation [PMID:19282482, PMID:19262565, PMID:26116705, PMID:22820736, PMID:29358331]. A recurrent theme is regulation of the Hippo effector YAP, where SETD7 methylates YAP at K494 to enforce cytoplasmic retention, linking it to intestinal progenitor control, Wnt/β-catenin crosstalk, and cardiomyocyte antioxidant gene expression [PMID:23850191, PMID:27046831, PMID:35709329]. SETD7 also restrains heterochromatin and DNA-damage responses by methylating SUV39H1, ARTD1/PARP1, and UHRF1 [PMID:23509280, PMID:24088713, PMID:30357346], and it modulates mitosis by dimethylating PLK1 to dampen its kinase activity at kinetochores [PMID:31863092]. Beyond catalysis, SETD7 functions as a reader of H3K36 methylation to drive stage-specific transcription during cardiac differentiation, associating with SWI/SNF and NKX2.5 [PMID:29499155]. Its own abundance and recruitment are set by SENP3-mediated deSUMOylation and TRIM21-mediated proteasomal degradation [PMID:31141694, PMID:32102992], and the selective inhibitor (R)-PFI-2 phenocopies genetic loss [PMID:25136132]. The requirement for SETD7-mediated p53 K372 methylation in the DNA-damage response, originally established in knockout MEFs, was not reproduced in two independent knockout strains [PMID:18280244, PMID:21855806, PMID:21855805].","teleology":[{"year":2002,"claim":"Established SETD7 as a histone methyltransferase and defined its first transcriptional mechanism, answering what enzymatic activity the protein carried.","evidence":"Biochemical isolation with in vitro HMT assays and cross-inhibition assays against Suv39h1 and G9a","pmids":["11850410"],"confidence":"High","gaps":["Did not determine the relative importance of histone versus non-histone targets in cells","Genomic targets of H3K4 monomethylation not mapped"]},{"year":2003,"claim":"Explained the structural basis for why SETD7 is exclusively a mono-methylase, answering how product specificity is enforced.","evidence":"High-resolution X-ray crystallography of the ternary SET7/9-H3 peptide-AdoMet complex with solution validation","pmids":["12540855"],"confidence":"High","gaps":["Static structure did not reveal catalytic proton-transfer dynamics","Did not address how diverse non-histone substrates are accommodated"]},{"year":2004,"claim":"Showed SETD7 methylates a non-histone protein (TAF10) to alter a protein-protein interaction, opening the broader non-histone substrate paradigm.","evidence":"In vitro methylation, affinity pull-down, reporter assays, and TAF10-null complementation with a methylation-deficient mutant","pmids":["15099517"],"confidence":"High","gaps":["Scope of non-histone substrate range still undefined","Promoter selectivity mechanism not resolved"]},{"year":2006,"claim":"Defined the SETD7 substrate-recognition consensus motif, providing a predictive rule for substrate identification.","evidence":"X-ray crystallography of multiple substrate peptide complexes plus mutagenesis and in vitro methylation assays","pmids":["16415881"],"confidence":"High","gaps":["Motif alone does not predict in vivo methylation given modification-dependent inhibition","Cellular relevance of newly identified substrates such as TAF7 not tested in vivo"]},{"year":2007,"claim":"Identified Tyr-335 as the catalytic base and described the conformational change underpinning mono-methylation, refining the catalytic mechanism.","evidence":"QM/MM molecular dynamics and free-energy simulations correlated with Y305F and Y335F mutant analysis","pmids":["17517655"],"confidence":"Medium","gaps":["Primarily computational; full kinetic dissection not performed","Mechanism inferred from histone substrate may differ for non-histone targets"]},{"year":2008,"claim":"Linked SETD7 to receptor and inflammatory transcription factor regulation by methylating ERα and NF-κB to control stability and promoter recruitment.","evidence":"In vitro methylation, crystallography of the SET7-ER complex, Co-IP, ChIP, and siRNA knockdown in monocytes","pmids":["18471979","18650421"],"confidence":"High","gaps":["Whether ERα stabilization and NF-κB coactivation generalize across cell types unresolved","Interplay with other ERα/NF-κB modifications not mapped"]},{"year":2008,"claim":"Reported that SETD7 methylates p53 at K372 and that this is required for Tip60 binding, p53 acetylation, and tumor suppression — a defining proposed in vivo role.","evidence":"Set7/9 knockout mouse MEFs, DNA damage assays, Tip60-p53 Co-IP, and transformation assays","pmids":["18280244"],"confidence":"High","gaps":["Subsequently contradicted by independent knockout strains","Strain background and assay conditions differed from later studies"]},{"year":2009,"claim":"Extended SETD7 control to DNA methylation machinery and NF-κB turnover by methylating DNMT1 and RelA to trigger their proteasomal degradation, establishing methylation as a degradation signal.","evidence":"Co-IP, in vitro methylation, mass spectrometry site mapping, proteasome inhibitor and knockdown experiments","pmids":["19282482","19262565"],"confidence":"High","gaps":["E3 ligases coupling these methylation marks to degradation not identified","Cell-cycle coupling of DNMT1 turnover only partially characterized"]},{"year":2010,"claim":"Showed SETD7 methylates signaling and viral substrates (AR, HIV-1 Tat) with opposite functional consequences (activation), broadening its regulatory repertoire including RNA-associated functions.","evidence":"In vitro methylation, ChIP, TAR RNA binding assays, and reporter assays with methylation-deficient mutants","pmids":["20959290","21273441","20227666"],"confidence":"High","gaps":["Mechanism by which a single mark activates AR yet destabilizes other substrates not unified","Physiological role of Tat methylation in viral latency not established"]},{"year":2011,"claim":"Two independent knockout strains found SETD7 dispensable for the p53 DNA-damage response, directly challenging the 2008 model and exposing context dependence of non-histone methylation.","evidence":"Two independent Set7/9 knockout mouse strains with comprehensive DNA-damage phenotyping and p53 acetylation analysis","pmids":["21855806","21855805"],"confidence":"High","gaps":["Source of discrepancy with the original study unresolved","Does not exclude tissue- or stress-specific p53 regulation"]},{"year":2011,"claim":"Defined an indirect p53 regulatory axis and systematic substrate expansion, showing SETD7 can act through SIRT1 sequestration and methylate numerous additional proteins under modification-dependent constraints.","evidence":"Reciprocal Co-IP for SIRT1, peptide-array screening with in vitro/in vivo validation of nine non-histone substrates, and FoxO3 MS site mapping","pmids":["21245319","21276944","22820736"],"confidence":"Medium","gaps":["Many array-identified substrates lack functional follow-up","In vivo relevance of SIRT1 and FoxO3 effects from single labs"]},{"year":2012,"claim":"Connected SETD7 to heterochromatin integrity and developmental signaling by methylating SUV39H1, FXR, and the Hippo effector YAP, establishing YAP cytoplasmic retention as a key in vivo function.","evidence":"Mass spectrometry, in vitro methylation, micrococcal nuclease assays, EMSA/reporter assays, and a Set7 knockout intestinal progenitor model","pmids":["23509280","22345554","23850191"],"confidence":"High","gaps":["How SETD7 balances chromatin-relaxing versus signaling roles in vivo unclear","Upstream signals directing YAP methylation not defined"]},{"year":2013,"claim":"Revealed SETD7 roles in DNA-damage chromatin responses and TGF-β/fibrosis control by methylating ARTD1/PARP1 and Smad7, with the latter coupling methylation to Arkadia-dependent degradation in vivo.","evidence":"In vitro methylation, laser-induced damage recruitment imaging, ubiquitination assays, and a Set9 knockout lung-fibrosis mouse model","pmids":["24088713","27292644"],"confidence":"High","gaps":["Direct contribution of ARTD1 methylation to repair outcomes not quantified","Pharmacological translation of the fibrosis finding untested in the timeline"]},{"year":2014,"claim":"Delivered a potent selective chemical probe ((R)-PFI-2) that occupies the substrate groove and phenocopies genetic loss, enabling acute interrogation of SETD7 function.","evidence":"Ki determination, crystallography of the inhibitor complex, chemoproteomics, and cell-based YAP localization assays","pmids":["25136132"],"confidence":"High","gaps":["Probe does not distinguish individual substrate contributions","Off-target methyltransferase activity in complex tissues not exhaustively excluded"]},{"year":2014,"claim":"Implicated SETD7 in cell-cycle and survival transcription programs through E2F1 coactivation and a proposed Mdm2 interaction, linking it to genotoxic stress responses.","evidence":"Co-IP, ChIP, gene expression and G1/S progression assays across cancer cell lines","pmids":["25124555","26317544"],"confidence":"Medium","gaps":["Mdm2 regulation rests on a single low-confidence Co-IP/correlation study without mechanistic depth","Direct versus indirect histone effects at E2F1 promoters not separated"]},{"year":2015,"claim":"Expanded SETD7 control to metabolic, hypoxic, and developmental transcription factors (Pdx1, HIF-1α/2α, Gli3, β-catenin) with marks driving either activation, repression, or GSK-3β-coupled degradation.","evidence":"In vitro methylation with MS/mutagenesis, ChIP at HREs, half-life assays, and conditional/whole-body knockout phenotypes","pmids":["25713082","25897119","27146893","26116705"],"confidence":"High","gaps":["Why the same enzyme activates some factors and degrades others remains mechanistically unexplained","Tissue specificity of these competing outcomes not systematically tested"]},{"year":2016,"claim":"Integrated SETD7 into Wnt-Hippo crosstalk and additional transcription-factor regulation, showing YAP methylation gates β-catenin nuclear accumulation and tumorigenesis while YY1 methylation tunes its DNA binding.","evidence":"SETD7 knockout intestinal tumor/regeneration model, YAP-AXIN1-β-catenin complex Co-IP, EMSA, and ChIP","pmids":["27046831","26902152"],"confidence":"High","gaps":["Stoichiometry and dynamics of the YAP-AXIN1-β-catenin-SETD7 complex unresolved","YY1 regulation from a single lab"]},{"year":2018,"claim":"Established a catalysis-independent reader function and additional stability control, with SETD7 binding H3K36me to drive cardiac differentiation and methylating SOX2 within a writer-eraser-reader module.","evidence":"ChIP-seq, Co-IP with SWI/SNF and NKX2.5, enzyme-dead mutant analysis, and SOX2 stability assays with LSD1/PHF20L1 knockdown","pmids":["29499155","29358331"],"confidence":"High","gaps":["Structural basis of H3K36me reading not defined","Generality of the catalysis-independent role beyond cardiac lineage untested"]},{"year":2018,"claim":"Identified Rpl29 K5 as a SETD7-exclusive mark and a cellular biomarker of enzyme activity, providing a tool to monitor inhibition.","evidence":"In vitro methylation, methylation-specific antibody, subcellular fractionation, and (R)-PFI-2 response","pmids":["29959229"],"confidence":"Medium","gaps":["Functional consequence of Rpl29 methylation limited to localization, with no effect on translation","Single lab"]},{"year":2019,"claim":"Defined how SETD7 activity is positioned and the breadth of its DNA-repair and chromatin roles, showing SENP3 deSUMOylation recruits it to muscle gene loci and that it methylates UHRF1 to promote homologous recombination.","evidence":"Co-IP, deSUMOylation and polyubiquitination assays, ChIP, phosphorylation-mutant analysis, and HR assays","pmids":["31141694","30357346"],"confidence":"Medium","gaps":["How SUMOylation status mechanistically gates SETD7 catalysis unclear","UHRF1-PCNA repair axis from a single lab"]},{"year":2020,"claim":"Showed SETD7 regulates mitosis directly by dimethylating PLK1 to dampen kinase activity at kinetochores, expanding its reach beyond transcription.","evidence":"In vitro methylation, K191 mutagenesis, kinase activity assays, and kinetochore-microtubule attachment/mitosis assays with inhibitor","pmids":["31863092"],"confidence":"Medium","gaps":["This is a dimethylation event, atypical for the canonical mono-methylase, and structural basis is unexplained","Single lab"]},{"year":2016,"claim":"Identified TRIM21 as a proteasomal negative regulator of SETD7, defining how the enzyme's own abundance is controlled in cancer contexts.","evidence":"Mass spectrometry, Co-IP, GST pulldown, ubiquitination assays, and ChIP-seq with xenograft analysis","pmids":["32102992"],"confidence":"Medium","gaps":["Signals triggering TRIM21-mediated SETD7 degradation not defined","Single lab"]},{"year":2021,"claim":"Linked SETD7 to neurodegeneration-associated Tau modification, with methylation at K132 priming K130 and correlating with pathology stage.","evidence":"Mass spectrometry in human AD brain, methylation-specific antibodies, knockdown/inhibitor studies, and subcellular fractionation","pmids":["34215303"],"confidence":"Medium","gaps":["Causal contribution of Tau methylation to pathology not established","Single lab"]},{"year":2023,"claim":"Demonstrated a translational cardioprotective role, with SETD7-mediated YAP methylation impairing antioxidant gene expression during energy deprivation and (R)-PFI-2 preventing ischemia/reperfusion injury.","evidence":"Cardiomyocyte energy-deprivation culture, SETD7 knockout I/R mouse model, pharmacological inhibition, and YAP localization/mtROS readouts","pmids":["35709329"],"confidence":"High","gaps":["Whether benefit derives solely from YAP versus other cardiac substrates not isolated","Long-term safety of SETD7 inhibition not addressed"]},{"year":null,"claim":"It remains unresolved what governs whether a given SETD7 methylation event stabilizes versus degrades a substrate, or activates versus represses transcription, and how catalytic versus reader functions are partitioned across tissues.","evidence":"No single study in the timeline reconciles the opposing functional outcomes of SETD7 methylation across its many substrates","pmids":[],"confidence":"Low","gaps":["No unifying rule predicting activating versus degradative outcomes","Endogenous substrate priority and stoichiometry largely unquantified","Reader (H3K36me) versus writer contributions separated only in cardiac differentiation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,5,8,9,11,18,29]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,5,8,9,11,18,29,37]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,20,32]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[12,36,40]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,8,30,32]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[17,39]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,5,11,19,28]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,22,26,27,29,30,39]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[18,21,35]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[25,37]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[14,17,28,32]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8,9,29,33]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,9]}],"complexes":["YAP-AXIN1-β-catenin complex"],"partners":["YAP1","DNMT1","RELA","SUV39H1","MYOD","SIRT1","SENP3","TRIM21"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WTS6","full_name":"Histone-lysine N-methyltransferase SETD7","aliases":["Histone H3-K4 methyltransferase SETD7","H3-K4-HMTase SETD7","Lysine N-methyltransferase 7","SET domain-containing protein 7","SET7/9"],"length_aa":366,"mass_kda":40.7,"function":"Histone methyltransferase that specifically monomethylates 'Lys-4' of histone H3 (PubMed:11779497, PubMed:11850410, PubMed:12540855, PubMed:12588998, PubMed:16141209). H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation (PubMed:12540855, PubMed:12588998, PubMed:16141209). Plays a central role in the transcriptional activation of genes such as collagenase or insulin (PubMed:12588998, PubMed:16141209). Recruited by IPF1/PDX-1 to the insulin promoter, leading to activate transcription (PubMed:16141209). Also has methyltransferase activity toward non-histone proteins such as CGAS, p53/TP53, TAF10, and possibly TAF7 by recognizing and binding the [KR]-[STA]-K in substrate proteins (PubMed:15099517, PubMed:15525938, PubMed:16415881, PubMed:35210392). Monomethylates 'Lys-189' of TAF10, leading to increase the affinity of TAF10 for RNA polymerase II (PubMed:15099517, PubMed:16415881). Monomethylates 'Lys-372' of p53/TP53, stabilizing p53/TP53 and increasing p53/TP53-mediated transcriptional activation (PubMed:15525938, PubMed:16415881, PubMed:17108971). Monomethylates 'Lys-491' of CGAS, promoting interaction between SGF29 and CGAS (By similarity)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q8WTS6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SETD7","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SETD7","total_profiled":1310},"omim":[{"mim_id":"621524","title":"WD REPEAT- AND SOCS BOX-CONTAINING PROTEIN 2; WSB2","url":"https://www.omim.org/entry/621524"},{"mim_id":"620050","title":"PHD FINGER PROTEIN 20-LIKE 1; PHF20L1","url":"https://www.omim.org/entry/620050"},{"mim_id":"616424","title":"SET DOMAIN-CONTAINING PROTEIN 6; SETD6","url":"https://www.omim.org/entry/616424"},{"mim_id":"610506","title":"PAF1 HOMOLOG, PAF1/RNA POLYMERASE II COMPLEX COMPONENT; PAF1","url":"https://www.omim.org/entry/610506"},{"mim_id":"610091","title":"WD REPEAT- AND SOCS BOX-CONTAINING PROTEIN 1; WSB1","url":"https://www.omim.org/entry/610091"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"},{"location":"Nucleoli rim","reliability":"Enhanced"},{"location":"Mitotic chromosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SETD7"},"hgnc":{"alias_symbol":["KIAA1717","SET7","SET7/9","Set9","KMT7"],"prev_symbol":[]},"alphafold":{"accession":"Q8WTS6","domains":[{"cath_id":"2.20.110.10","chopping":"8-112","consensus_level":"medium","plddt":95.1003,"start":8,"end":112},{"cath_id":"2.20.110.10","chopping":"125-193","consensus_level":"medium","plddt":97.4214,"start":125,"end":193},{"cath_id":"2.170.270.10","chopping":"209-339","consensus_level":"high","plddt":96.637,"start":209,"end":339}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WTS6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WTS6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WTS6-F1-predicted_aligned_error_v6.png","plddt_mean":94.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SETD7","jax_strain_url":"https://www.jax.org/strain/search?query=SETD7"},"sequence":{"accession":"Q8WTS6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WTS6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WTS6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WTS6"}},"corpus_meta":[{"pmid":"11850410","id":"PMC_11850410","title":"Set9, a novel histone H3 methyltransferase that facilitates transcription by precluding histone tail modifications required for heterochromatin formation.","date":"2002","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/11850410","citation_count":454,"is_preprint":false},{"pmid":"12540855","id":"PMC_12540855","title":"Structure and catalytic mechanism of the human histone methyltransferase SET7/9.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12540855","citation_count":308,"is_preprint":false},{"pmid":"18650421","id":"PMC_18650421","title":"Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-kappaB-dependent inflammatory genes. 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This methylation precludes association of the NuRD histone deacetylase complex with the H3 tail, and also impairs Suv39h1-mediated methylation at H3-K9, thereby promoting transcription activation.\",\n      \"method\": \"Biochemical isolation, in vitro histone methyltransferase assay, histone tail binding assay, cross-inhibition assay with Suv39h1 and G9a\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with multiple orthogonal biochemical assays; foundational paper replicated by subsequent studies\",\n      \"pmids\": [\"11850410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of a ternary complex of human SET7/9 with a histone H3 peptide and cofactor (AdoMet) revealed that the peptide substrate and cofactor bind on opposite surfaces of the enzyme, the target lysine inserts its side chain into a narrow channel connecting the two surfaces, and SET7/9 is exclusively a mono-methylase due to active-site geometry.\",\n      \"method\": \"High-resolution X-ray crystallography of ternary complex; solution studies confirming mono-methylase activity\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of ternary complex with functional validation; landmark structural study\",\n      \"pmids\": [\"12540855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SET9 (SETD7) monomethylates the TBP-associated factor TAF10 at a single lysine in its histone-fold domain (loop 2 region), and this methylation increases TAF10 affinity for RNA polymerase II, potentiating transcription of a subset of TAF10-dependent genes in a promoter-specific manner.\",\n      \"method\": \"In vitro methyltransferase assay, affinity pull-down, reporter assays, TAF10-null cell complementation with methylation-deficient mutant\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro methylation assay plus mutagenesis plus cell-based rescue; multiple orthogonal methods in one study\",\n      \"pmids\": [\"15099517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structures of SET7/9 bound to TAF10 and other substrate peptides revealed that the enzyme recognizes a conserved K/R-S/T/A motif preceding the target lysine, and has preference for aspartates/asparagines C-terminal to the target lysine, defining the substrate-specificity consensus motif. TAF7 was identified as a novel substrate (methylated at Lys5 in vitro) using this motif.\",\n      \"method\": \"X-ray crystallography, substrate peptide mutagenesis, in vitro methyltransferase assays with multiple substrates\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures plus mutagenesis plus in vitro assays across multiple substrates\",\n      \"pmids\": [\"16415881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"QM/MM molecular dynamics simulations of SET7/9 identified Tyr-335 as the general base for deprotonation of the methylated lysine after AdoHcy dissociation, and showed that conformational changes bring Y335 to the target lysine for proton abstraction, explaining mono-methylase product specificity. Y305F and Y335F mutants were analyzed to support the mechanism.\",\n      \"method\": \"Quantum mechanical/molecular mechanical (QM/MM) molecular dynamics and free-energy simulations; mutant analysis (Y305F, Y335F)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 (computational with mutant analysis) / Moderate — rigorous simulations with experimental mutant correlation but primarily computational\",\n      \"pmids\": [\"17517655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SETD7 directly methylates estrogen receptor alpha (ERα) at lysine 302. SET7-mediated K302 methylation stabilizes ERα protein and is required for efficient recruitment of ERα to its target gene promoters and their transactivation. A breast cancer-associated mutation K303R alters K302 methylation in vitro and in vivo. Crystal structure of the SET7-ER peptide complex revealed the molecular basis of recognition.\",\n      \"method\": \"In vitro methyltransferase assay, X-ray crystallography of SET7-ER peptide complex, Co-IP, ChIP, mutagenesis, K303R cancer mutation analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro methylation plus mutagenesis plus chromatin recruitment assays in one study\",\n      \"pmids\": [\"18471979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SET7/9 acts as a novel coactivator of NF-κB. SET7/9 knockdown in monocytes inhibits TNF-α-induced H3K4 methylation at NF-κB target gene promoters, reduces NF-κB p65 recruitment to those promoters, and attenuates inflammatory gene expression and monocyte adhesion.\",\n      \"method\": \"siRNA knockdown, ChIP, gene expression analysis (microarray), monocyte adhesion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional KD assays in multiple contexts, single lab\",\n      \"pmids\": [\"18650421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Set7/9 methylates p53 at K369 (mouse)/K372 (human) in vivo. Cells from Set7/9 knockout mice fail to methylate p53 K369, cannot induce p53 downstream targets upon DNA damage, and are predisposed to oncogenic transformation. Mechanistically, Set7/9-mediated p53 methylation is required for binding of the acetyltransferase Tip60 to p53 and for subsequent p53 acetylation.\",\n      \"method\": \"Set7/9 knockout mouse generation, MEF-based DNA damage assays, Co-IP (Tip60-p53), p53 acetylation analysis, transformation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic knockout mouse model with multiple orthogonal functional readouts and mechanistic Co-IP\",\n      \"pmids\": [\"18280244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SET7 directly interacts with DNMT1, colocalizes with it, and specifically monomethylates DNMT1 at Lys-142. This methylation promotes proteasome-mediated DNMT1 degradation, peaking during S and G2 phases. SET7 overexpression decreases DNMT1 levels; SET7 siRNA knockdown stabilizes DNMT1.\",\n      \"method\": \"Co-IP, colocalization (immunofluorescence), in vitro methyltransferase assay, proteasome inhibitor experiments, siRNA KD, SET7 overexpression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct interaction confirmed by Co-IP and pulldown, in vitro methylation assay, gain- and loss-of-function experiments\",\n      \"pmids\": [\"19282482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Set9 (SETD7) physically associates with the RelA subunit of NF-κB and monomethylates RelA at lysine residues 314 and 315 in vitro and in vivo. This methylation inhibits NF-κB action by inducing proteasome-mediated degradation of promoter-associated RelA, limiting the duration of NF-κB target gene expression.\",\n      \"method\": \"Co-IP, in vitro methyltransferase assay, mutational analysis, mass spectrometry, siRNA KD, reporter assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mass spectrometry identification of methylation sites, in vitro assay, mutagenesis, and cellular functional validation\",\n      \"pmids\": [\"19262565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Set7/9 (KMT7) monomethylates lysine 51 in the RNA-binding domain of HIV-1 Tat. Set7/9 associates with the HIV promoter in vivo, binds TAR RNA by itself and in complex with Tat and P-TEFb. Knockdown of Set7/9 suppresses Tat transactivation in a methylation-dependent manner (K51A Tat is refractory to Set7/9 KD).\",\n      \"method\": \"In vitro methyltransferase assay, ChIP, RNA binding assay (TAR RNA), siRNA KD, luciferase reporter assay with K51A mutant\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro methylation, RNA binding, ChIP, and genetic validation with methylation-deficient mutant in one study\",\n      \"pmids\": [\"20227666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SETD7 directly methylates and regulates the androgen receptor (AR). SET9 methylates AR at lysine 632 (also reported as K630 in a parallel study), which is necessary for enhancing AR transcriptional activity by facilitating inter-domain N-C communication and recruitment to androgen-target gene promoters.\",\n      \"method\": \"In vitro methyltransferase assay, Co-IP, ChIP, mutagenesis (K632A), N-C interaction assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct methylation demonstrated in vitro and in vivo with mutagenesis and functional ChIP assays; replicated by independent lab (PMID:21273441)\",\n      \"pmids\": [\"20959290\", \"21273441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Set7/9 interacts with SIRT1 both in vitro and in vivo. Upon DNA damage, Set7/9-SIRT1 interaction is enhanced, suppressing SIRT1-p53 interaction and abrogating SIRT1-mediated p53 deacetylation, thereby promoting p53-mediated transactivation. This regulation operates in addition to direct p53 methylation.\",\n      \"method\": \"Co-IP (in vitro and in vivo), p53 acetylation analysis, SIRT1 methylation analysis, reporter assays, DNA damage response assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional assays in single lab\",\n      \"pmids\": [\"21245319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Two independent Set7/9 knockout mouse strains showed that Set7/9 is dispensable for p53-dependent cell cycle arrest, apoptosis, and p53 acetylation following DNA damage or oncogene activation in vivo, contradicting the earlier finding (PMID:18280244) that p53 methylation by Set7/9 is required for p53 activation.\",\n      \"method\": \"Independent Set7/9 knockout mouse strain, DNA damage assays (irradiation, genotoxic agents), p53 target gene expression, p53 acetylation analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent knockout mouse strains (PMIDs 21855806 and 21855805) with comprehensive in vivo phenotypic analysis yielding negative results\",\n      \"pmids\": [\"21855806\", \"21855805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Set7 directly interacts with MyoD and promotes skeletal muscle differentiation. Set7 knockdown or dominant-negative expression impairs myoblast differentiation with decreased H3K4me1, reduced expression of myocyte enhancer factor 2 and contractile proteins, and myofibril assembly defects. Set7 activates muscle genes by precluding Suv39h1-mediated H3K9 methylation on myogenic gene promoters.\",\n      \"method\": \"Co-IP (Set7-MyoD), siRNA KD, dominant-negative overexpression, ChIP (H3K4me1, H3K9me), differentiation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, KD functional phenotype; single lab\",\n      \"pmids\": [\"21859860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Set9 directly methylates FoxO3 at lysine 271 (identified by tandem mass spectrometry and methyl-specific antibody). Set9-mediated FoxO3 methylation decreases FoxO3 protein stability while moderately increasing its transcriptional activity.\",\n      \"method\": \"In vitro methyltransferase assay, tandem mass spectrometry, methyl-specific antibody, protein stability assay\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro methylation confirmed by MS and methyl-specific antibody, functional stability assay; single lab\",\n      \"pmids\": [\"22820736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SET7/9 can methylate multiple new peptide substrates from human proteins. Confirmed methylation of nine nonhistone proteins (AKA6, CENPC1, MeCP2, MINT, PPARBP, ZDH8, Cullin1, IRF1, TTK) and H2A and H2B in vitro and in vivo. Phosphorylation of substrate proteins adjacent to the target lysine inhibits SET7/9 methylation. MINT protein can be dimethylated by SET7/9 showing context-dependent product specificity.\",\n      \"method\": \"Peptide array methylation, in vitro methyltransferase assays with protein domains, in vivo methylation validation with antibodies\",\n      \"journal\": \"Chemistry & biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — systematic peptide array and in vitro/in vivo protein methylation confirmed for multiple substrates; single lab\",\n      \"pmids\": [\"21276944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Set7 (Setd7) monomethylates YAP at lysine 494. This methylation is critical for cytoplasmic retention of YAP. Set7 knockout mice have a larger intestinal progenitor compartment with increased YAP target gene expression, placing Set7-mediated YAP methylation as a regulatory checkpoint in the Hippo pathway.\",\n      \"method\": \"Set7 knockout mouse model, intestinal progenitor analysis, in vitro methyltransferase assay, YAP subcellular localization studies, YAP target gene expression\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse genetics combined with mechanistic in vitro methylation and subcellular localization studies; replicated by subsequent work (PMID:27046831, 35709329)\",\n      \"pmids\": [\"23850191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SET7/9 directly methylates SUV39H1 at lysines 105 and 123 (identified by mass spectrometry and methyl-specific antibodies). Methylation dramatically down-regulates SUV39H1 methyltransferase activity, leading to decreased H3K9 trimethylation in heterochromatin, heterochromatin relaxation (increased Sat2 and α-Sat expression), and genome instability in response to DNA damage.\",\n      \"method\": \"Co-IP, GST pulldown, in vitro methyltransferase assay, mass spectrometry, methyl-specific antibody, micrococcal nuclease sensitivity assay, immunofluorescence\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mass spectrometry identification of methylation sites, in vitro and in vivo validation, mechanistic functional readout; multiple orthogonal methods\",\n      \"pmids\": [\"23509280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SET7/9 directly methylates the farnesoid X receptor (FXR) at lysine 206 in vivo and in vitro. Methylation enhances FXR/RXRα binding to the FXRE and potentiates transactivation of FXR target genes (SHP, BSEP). Methylation-deficient K206R mutant FXR shows impaired transactivation; SET7/9 methyltransferase-dead mutant is also inactive.\",\n      \"method\": \"In vitro methyltransferase assay, Co-IP, GST pulldown, mammalian two-hybrid, EMSA, luciferase reporter assay, K206R mutagenesis, siRNA KD\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including in vitro methylation, EMSA, mutagenesis, and reporter assays in one study\",\n      \"pmids\": [\"22345554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SET7/9 methylates histone H1.4 at multiple lysine residues (K121, K129, K159, K171, K177, K192) in KAK motifs of the C-terminal domain. ADP-ribosylation of H3 by ARTD1 prevents H3 methylation by SET7/9 but allows subsequent SET7/9 methylation of H1. H1 and H3 compete for SET7/9-dependent methylation, revealing substrate competition as a regulatory mechanism.\",\n      \"method\": \"In vitro methyltransferase assay with isolated histones, mass spectrometry identification of methylation sites, competition assays\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro assays with mass spectrometry site identification; single lab, mechanistic follow-up limited\",\n      \"pmids\": [\"23289424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SET7/9 directly methylates ARTD1 (PARP1) at K508 in vitro and in vivo. ARTD1 methylation by SET7/9 enhances poly-ADP-ribose (PAR) synthesis upon oxidative stress in vivo, and promotes ARTD1 recruitment to sites of laser-induced DNA damage in a SET7/9-dependent manner. ARTD1 auto-modification inhibits its methylation by SET7/9.\",\n      \"method\": \"In vitro methyltransferase assay, in vivo methylation detection, laser irradiation/PAR formation assay, live-cell imaging of ARTD1 recruitment\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro methylation plus in vivo functional readout; single lab\",\n      \"pmids\": [\"24088713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Negative regulation of TGF-β signaling: Set9 methylates Smad7 (an inhibitory TGF-β effector), promoting Smad7 interaction with the E3 ligase Arkadia and subsequent ubiquitination-dependent degradation of Smad7. Set9 depletion or pharmacological inhibition elevates Smad7 levels and inhibits TGF-β-dependent extracellular matrix gene expression. Set9-deficient mice show severely compromised lung fibrosis.\",\n      \"method\": \"In vitro methyltransferase assay, Co-IP (Smad7-Arkadia), ubiquitination assay, Set9 KO mouse model of pulmonary fibrosis (bleomycin/Ad-TGF-β), siRNA and pharmacological inhibitor studies\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro methylation, Co-IP, ubiquitination assay, in vivo mouse model; multiple orthogonal methods\",\n      \"pmids\": [\"27292644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"(R)-PFI-2 was identified as a potent (Ki = 0.33 nM), selective, cofactor-dependent, substrate-competitive inhibitor of SETD7. Crystal structure showed it occupies the substrate peptide binding groove including the lysine-binding channel and contacts the methyl group of SAM. In murine embryonic fibroblasts, (R)-PFI-2 phenocopied Setd7 deficiency on Hippo pathway signaling via YAP modulation; in confluent MCF7 cells it rapidly altered YAP localization.\",\n      \"method\": \"Biochemical inhibitor characterization (Ki determination), X-ray crystallography, chemoproteomics (biotinylated probe competition), cell-based YAP localization assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, biochemical Ki, chemoproteomics, and cell-based phenocopy of genetic KO in one study\",\n      \"pmids\": [\"25136132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Set7/9 physically interacts with Mdm2 and regulates expression of Mdm2 at the transcriptional level, affecting the DNA damage response. Multiple cancer cell lines with inverse expression of Set7/9 and Mdm2 show diminished survival in response to genotoxic stress.\",\n      \"method\": \"Co-IP, gene expression analysis, cell viability assays under genotoxic stress, bioinformatics\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and expression correlation; limited mechanistic depth in abstract\",\n      \"pmids\": [\"26317544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Set7/9 is a critical co-activator of E2F1-dependent transcription in response to DNA damage. Set7/9 indirectly modulates histone modifications at E2F1-dependent gene promoters, promotes CCNE1 expression (proliferation), and represses TP73 gene expression (anti-apoptotic). Cell cycle progression through G1/S checkpoint depends on threshold expression of both E2F1 and Set7/9.\",\n      \"method\": \"Co-IP, ChIP, gene expression analysis, cell biology assays (G1/S progression), bioinformatics across lung tumor cell lines\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-based histone modification analysis plus functional cell cycle assays; single lab\",\n      \"pmids\": [\"25124555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Set7 methylates HIF-1α at lysine 32 and HIF-2α at lysine K29, inhibiting HIF-α transcriptional activity by impairing occupancy of HIF-α on hypoxia response elements of target gene promoters. Set7-null fibroblasts and Set7 KD/inhibited cells show upregulated HIF target genes and increased glucose uptake.\",\n      \"method\": \"In vitro methyltransferase assay, ChIP (HIF-α at HRE), Set7 KO fibroblasts, shRNA KD, Set7 inhibitor treatment, glucose uptake assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro methylation plus ChIP plus KO/KD functional phenotype; single lab\",\n      \"pmids\": [\"25897119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Set7 monomethylates Gli3 full-length (but not truncated form) at K436 and K595. Methylation at K436 increases Gli3 stability and methylation at K595 increases Gli3 DNA binding ability, together enhancing Shh signaling activation and contributing to tumor growth/metastasis in non-small cell lung cancer.\",\n      \"method\": \"In vitro methyltransferase assay, mutagenesis (K436A, K595A), protein stability assay, DNA binding assay, Shh target gene expression, in vitro/in vivo tumor assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro methylation with mutagenesis and functional stability/DNA binding readouts; single lab\",\n      \"pmids\": [\"27146893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Set7/9 methylates the transcription factor Pdx1 at K123 and K131 (identified by mass spectrometry and mutagenesis of purified proteins). K131 methylation (but not K123) is required for transcriptional augmentation by Set7/9. Conditional deletion of Set7/9 in β cells causes glucose intolerance and impaired glucose-stimulated insulin secretion with reduced Pdx1 target gene expression.\",\n      \"method\": \"In vitro methyltransferase assay, mass spectrometry, mutagenesis, luciferase reporter assay, conditional knockout mouse (Set(Δ)β), islet glucose-stimulated insulin secretion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — MS-identified methylation sites, mutagenesis, in vivo conditional KO with defined metabolic phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"25713082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SET7/9 directly methylates β-catenin at lysine 180 (identified by mutagenesis and mass spectrometry). Methylated β-catenin is recognized by GSK-3β for degradation. K180R mutant β-catenin has a longer half-life. SET7/9 depletion or K180R mutation enhances Wnt/β-catenin target gene expression and promotes cancer cell growth.\",\n      \"method\": \"Co-IP, in vitro methyltransferase assay, mutagenesis (K180R), mass spectrometry, protein half-life assay, luciferase reporter assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro methylation, MS site identification, mutagenesis, functional stability assay, and cellular gene expression; multiple orthogonal methods\",\n      \"pmids\": [\"26116705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SETD7-mediated methylation of YAP (K494) facilitates Wnt-induced nuclear accumulation of β-catenin. SETD7 is part of a complex containing YAP, AXIN1, and β-catenin. SETD7 is required for Wnt-driven intestinal tumorigenesis and regeneration, linking the Wnt/β-catenin and Hippo/YAP pathways.\",\n      \"method\": \"SETD7 KO mouse model (intestinal tumorigenesis/regeneration), Co-IP complex analysis (YAP-AXIN1-β-catenin-SETD7), β-catenin nuclear localization assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse tumor/regeneration model, complex Co-IP, mechanistic nuclear localization assays; builds on prior mechanistic work\",\n      \"pmids\": [\"27046831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SET7/9 methylates transcription factor YY1 at two lysine residues, K173 and K411. This methylation regulates YY1 DNA-binding activity in vitro and at specific genomic loci in cells, affecting YY1-regulated gene transcription and cell proliferation.\",\n      \"method\": \"In vitro methyltransferase assay, mutagenesis, EMSA (DNA binding), ChIP, luciferase reporter assay, cell proliferation assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro methylation, mutagenesis, EMSA, and ChIP; single lab\",\n      \"pmids\": [\"26902152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SETD7 controls cardiac differentiation by reading H3K36 marks independently of its enzymatic activity. During mesodermal formation, SETD7 associates with SWI/SNF chromatin-remodeling factors; in cardiac progenitors it associates with NKX2.5. SETD7 binds methylated H3K36 in gene bodies of target genes to facilitate RNA Pol II-dependent transcription.\",\n      \"method\": \"ChIP-seq, Co-IP (SETD7 with SWI/SNF and NKX2.5), enzymatic activity mutant analysis, H3K36me binding assay, differentiation assays from hPSCs\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genome-wide ChIP-seq, Co-IP with multiple co-factors, enzymatic-dead mutant used to separate reading from writing function; multiple orthogonal methods\",\n      \"pmids\": [\"29499155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SET7 methylates SOX2 at K119 (mouse)/K117 (human) and K42, triggering ubiquitin-dependent SOX2 proteolysis. LSD1 demethylase removes methyl groups from both sites preventing degradation, while PHF20L1 binds monomethylated K42 and K117 to protect SOX2 from proteolysis. SET7/LSD1/PHF20L1 dynamically regulate SOX2 stability in pluripotent stem cells.\",\n      \"method\": \"In vitro methyltransferase assay, methylation-specific antibody, Co-IP, siRNA KD (LSD1, PHF20L1), protein stability assay, SET7 inactivation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro methylation plus stability assays plus KD of reader/eraser; single lab\",\n      \"pmids\": [\"29358331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rpl29 lysine 5 (Rpl29K5) is methylated exclusively by Set7/9 and can be demethylated by Lsd1. Rpl29 methylation has no effect on global protein synthesis but affects Rpl29 subcellular localization. Rpl29K5 methylation was validated as a specific cellular biomarker for Set7/9 activity, responsive to (R)-PFI-2 inhibitor treatment.\",\n      \"method\": \"In vitro methyltransferase assay (substrate identification), methylation-specific antibody, subcellular fractionation, Set7/9 inhibitor treatment, global translation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro methylation, specific antibody validation, cellular inhibitor response; single lab\",\n      \"pmids\": [\"29959229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UHRF1 is methylated by SET7 and demethylated by LSD1. UHRF1 phosphorylation in S phase is a prerequisite for its interaction with SET7. SET7-mediated UHRF1 methylation catalyzes polyubiquitin chain conjugation to PCNA and promotes homologous recombination for DNA double-strand break repair. UHRF1 methylation is induced in response to DNA damage.\",\n      \"method\": \"In vitro methyltransferase assay, Co-IP, phosphorylation mutant analysis, polyubiquitination assay (PCNA), homologous recombination assay, cell viability assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro methylation, Co-IP, functional PCNA ubiquitination and HR assays; single lab\",\n      \"pmids\": [\"30357346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SUMO-specific isopeptidase SENP3 associates with SETD7 and deSUMOylates it. By recruiting SETD7 to the MyHC-II gene locus, SENP3 promotes SETD7 association with active RNA polymerase II and precludes opposing Suv39h1 activity. SENP3 is degraded in cachexia, impairing this SENP3-SETD7 regulatory axis, resulting in disrupted MyHC-II expression and disorganized sarcomeres.\",\n      \"method\": \"Co-IP (SENP3-SETD7), deSUMOylation assay, ChIP (SETD7 and Pol II at MyHC-II), SENP3 KD functional assay, cachexia model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, biochemical deSUMOylation, and ChIP-based mechanism; single lab\",\n      \"pmids\": [\"31141694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SETD7 methylates PLK1 at K191 (dimethylation), tuning down PLK1 kinase activity by limiting ATP utilization at kinetochores during early mitosis. Non-methylatable PLK1 K191 mutant or chemical inhibition of SETD7 causes mitotic arrest due to destabilized kinetochore-microtubule attachments, revealing that SETD7-mediated PLK1 methylation promotes dynamic kinetochore-microtubule attachments for accurate error correction.\",\n      \"method\": \"In vitro methyltransferase assay, mutagenesis (K191), PLK1 kinase activity assay, kinetochore-microtubule attachment assay, SETD7 inhibitor treatment, mitosis assay\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro methylation, mutagenesis, kinase activity assay, and cell biology phenotype; single lab\",\n      \"pmids\": [\"31863092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SETD7 methylates Tau at K132, an event that facilitates subsequent methylation at K130. Methylated Tau (identified by mass spectrometry in human AD brain) preferentially localizes to cell soma and nuclear fractions (absent from neurites) in hiPSC-derived neurons and mouse brain, and methylated Tau levels increase with Tau pathology stage.\",\n      \"method\": \"Mass spectrometry (human AD brain), methylation-specific antibody development, knockdown and inhibitor studies, subcellular fractionation, proteomics\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — MS identification in human tissue, specific antibody, KD/inhibitor validation, subcellular localization; single lab\",\n      \"pmids\": [\"34215303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SETD7 methylates the Hippo pathway effector YAP upon energy deprivation in cardiomyocytes, leading to YAP cytosolic retention and impaired transcription of antioxidant genes MnSOD and CAT. This impairment causes mitochondrial ROS accumulation, organelle swelling, and apoptosis. Pharmacological inhibition of SETD7 by (R)-PFI-2 restores YAP nuclear localization and prevents myocardial ischemia/reperfusion injury in mice.\",\n      \"method\": \"NRVM culture (energy deprivation), SETD7 KO mouse I/R injury model, (R)-PFI-2 pharmacological inhibition, YAP localization assay, MnSOD/CAT expression, mtROS measurement, LV function assay\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo genetic/pharmacological approaches with mechanistic YAP localization and antioxidant gene expression readouts; translational human tissue validation\",\n      \"pmids\": [\"35709329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRIM21 physically associates with SETD7 and functions as a major negative regulator upstream of SETD7 through a proteasome-dependent ubiquitination mechanism, leading to SETD7 degradation. SETD7 promotes breast cancer malignant processes via activation of RUNX2.\",\n      \"method\": \"Mass spectrometry, Co-IP, GST pulldown, ubiquitination assay, ChIP-seq, ChIP, cell functional assays, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, GST pulldown, and ubiquitination assay for TRIM21-SETD7 interaction/degradation; single lab\",\n      \"pmids\": [\"32102992\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SETD7 (SET7/9, KMT7) is a SET-domain lysine methyltransferase that acts exclusively as a mono-methylase (established by crystal structure): it methylates histone H3K4 to promote transcription by blocking NuRD deacetylase binding and Suv39h1-mediated H3K9 methylation, and it methylates a broad array of non-histone substrates—including p53, ERα, DNMT1, NF-κB RelA, AR, TAF10, YAP, β-catenin, PLK1, FXR, Pdx1, SIRT1, SUV39H1, Smad7, Tat, HIF-1α/2α, FoxO3, Gli3, SOX2, ARTD1, UHRF1, YY1, and Tau—with each methylation event regulating the substrate's stability, activity, protein–protein interactions, or subcellular localization; its own activity is controlled by SENP3-mediated deSUMOylation and TRIM21-mediated proteasomal degradation, and it additionally reads H3K36 methylation marks (independently of catalysis) to drive stage-specific transcription during cardiac differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SETD7 (SET7/9, KMT7) is a SET-domain protein lysine methyltransferase that controls transcription and signaling by depositing a single methyl mark on histone and, predominantly, non-histone substrates [#0, #1]. Active-site geometry restricts it to mono-methylation: a target lysine inserts into a narrow channel between the substrate and AdoMet binding surfaces, and Tyr-335 acts as the catalytic base that limits product to the mono-methyl state [#1, #4]. Substrate selection follows a defined K/R-S/T/A consensus preceding the target lysine, and methylation is suppressed when adjacent residues are phosphorylated or otherwise modified [#3, #16]. On chromatin, SETD7 monomethylates histone H3K4 to activate transcription by excluding the NuRD deacetylase complex and antagonizing Suv39h1-mediated H3K9 methylation [#0], a writer logic it reuses at myogenic promoters through direct interaction with MyoD [#14]. The dominant biology of SETD7, however, is the methylation of transcription factors and signaling proteins, where individual marks tune substrate stability, DNA binding, partner recruitment, or subcellular localization: it methylates ERα, AR, FXR, Pdx1, and Gli3 to enhance their promoter recruitment and transactivation [#5, #11, #19, #28, #27], while methylation of DNMT1, NF-κB RelA, β-catenin, FoxO3, and SOX2 directs them toward proteasomal degradation [#8, #9, #29, #15, #33]. A recurrent theme is regulation of the Hippo effector YAP, where SETD7 methylates YAP at K494 to enforce cytoplasmic retention, linking it to intestinal progenitor control, Wnt/β-catenin crosstalk, and cardiomyocyte antioxidant gene expression [#17, #30, #39]. SETD7 also restrains heterochromatin and DNA-damage responses by methylating SUV39H1, ARTD1/PARP1, and UHRF1 [#18, #21, #35], and it modulates mitosis by dimethylating PLK1 to dampen its kinase activity at kinetochores [#37]. Beyond catalysis, SETD7 functions as a reader of H3K36 methylation to drive stage-specific transcription during cardiac differentiation, associating with SWI/SNF and NKX2.5 [#32]. Its own abundance and recruitment are set by SENP3-mediated deSUMOylation and TRIM21-mediated proteasomal degradation [#36, #40], and the selective inhibitor (R)-PFI-2 phenocopies genetic loss [#23]. The requirement for SETD7-mediated p53 K372 methylation in the DNA-damage response, originally established in knockout MEFs, was not reproduced in two independent knockout strains [#7, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established SETD7 as a histone methyltransferase and defined its first transcriptional mechanism, answering what enzymatic activity the protein carried.\",\n      \"evidence\": \"Biochemical isolation with in vitro HMT assays and cross-inhibition assays against Suv39h1 and G9a\",\n      \"pmids\": [\"11850410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not determine the relative importance of histone versus non-histone targets in cells\", \"Genomic targets of H3K4 monomethylation not mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Explained the structural basis for why SETD7 is exclusively a mono-methylase, answering how product specificity is enforced.\",\n      \"evidence\": \"High-resolution X-ray crystallography of the ternary SET7/9-H3 peptide-AdoMet complex with solution validation\",\n      \"pmids\": [\"12540855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Static structure did not reveal catalytic proton-transfer dynamics\", \"Did not address how diverse non-histone substrates are accommodated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed SETD7 methylates a non-histone protein (TAF10) to alter a protein-protein interaction, opening the broader non-histone substrate paradigm.\",\n      \"evidence\": \"In vitro methylation, affinity pull-down, reporter assays, and TAF10-null complementation with a methylation-deficient mutant\",\n      \"pmids\": [\"15099517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Scope of non-histone substrate range still undefined\", \"Promoter selectivity mechanism not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the SETD7 substrate-recognition consensus motif, providing a predictive rule for substrate identification.\",\n      \"evidence\": \"X-ray crystallography of multiple substrate peptide complexes plus mutagenesis and in vitro methylation assays\",\n      \"pmids\": [\"16415881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Motif alone does not predict in vivo methylation given modification-dependent inhibition\", \"Cellular relevance of newly identified substrates such as TAF7 not tested in vivo\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified Tyr-335 as the catalytic base and described the conformational change underpinning mono-methylation, refining the catalytic mechanism.\",\n      \"evidence\": \"QM/MM molecular dynamics and free-energy simulations correlated with Y305F and Y335F mutant analysis\",\n      \"pmids\": [\"17517655\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Primarily computational; full kinetic dissection not performed\", \"Mechanism inferred from histone substrate may differ for non-histone targets\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked SETD7 to receptor and inflammatory transcription factor regulation by methylating ERα and NF-κB to control stability and promoter recruitment.\",\n      \"evidence\": \"In vitro methylation, crystallography of the SET7-ER complex, Co-IP, ChIP, and siRNA knockdown in monocytes\",\n      \"pmids\": [\"18471979\", \"18650421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ERα stabilization and NF-κB coactivation generalize across cell types unresolved\", \"Interplay with other ERα/NF-κB modifications not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Reported that SETD7 methylates p53 at K372 and that this is required for Tip60 binding, p53 acetylation, and tumor suppression — a defining proposed in vivo role.\",\n      \"evidence\": \"Set7/9 knockout mouse MEFs, DNA damage assays, Tip60-p53 Co-IP, and transformation assays\",\n      \"pmids\": [\"18280244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subsequently contradicted by independent knockout strains\", \"Strain background and assay conditions differed from later studies\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended SETD7 control to DNA methylation machinery and NF-κB turnover by methylating DNMT1 and RelA to trigger their proteasomal degradation, establishing methylation as a degradation signal.\",\n      \"evidence\": \"Co-IP, in vitro methylation, mass spectrometry site mapping, proteasome inhibitor and knockdown experiments\",\n      \"pmids\": [\"19282482\", \"19262565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligases coupling these methylation marks to degradation not identified\", \"Cell-cycle coupling of DNMT1 turnover only partially characterized\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed SETD7 methylates signaling and viral substrates (AR, HIV-1 Tat) with opposite functional consequences (activation), broadening its regulatory repertoire including RNA-associated functions.\",\n      \"evidence\": \"In vitro methylation, ChIP, TAR RNA binding assays, and reporter assays with methylation-deficient mutants\",\n      \"pmids\": [\"20959290\", \"21273441\", \"20227666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which a single mark activates AR yet destabilizes other substrates not unified\", \"Physiological role of Tat methylation in viral latency not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Two independent knockout strains found SETD7 dispensable for the p53 DNA-damage response, directly challenging the 2008 model and exposing context dependence of non-histone methylation.\",\n      \"evidence\": \"Two independent Set7/9 knockout mouse strains with comprehensive DNA-damage phenotyping and p53 acetylation analysis\",\n      \"pmids\": [\"21855806\", \"21855805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Source of discrepancy with the original study unresolved\", \"Does not exclude tissue- or stress-specific p53 regulation\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined an indirect p53 regulatory axis and systematic substrate expansion, showing SETD7 can act through SIRT1 sequestration and methylate numerous additional proteins under modification-dependent constraints.\",\n      \"evidence\": \"Reciprocal Co-IP for SIRT1, peptide-array screening with in vitro/in vivo validation of nine non-histone substrates, and FoxO3 MS site mapping\",\n      \"pmids\": [\"21245319\", \"21276944\", \"22820736\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many array-identified substrates lack functional follow-up\", \"In vivo relevance of SIRT1 and FoxO3 effects from single labs\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected SETD7 to heterochromatin integrity and developmental signaling by methylating SUV39H1, FXR, and the Hippo effector YAP, establishing YAP cytoplasmic retention as a key in vivo function.\",\n      \"evidence\": \"Mass spectrometry, in vitro methylation, micrococcal nuclease assays, EMSA/reporter assays, and a Set7 knockout intestinal progenitor model\",\n      \"pmids\": [\"23509280\", \"22345554\", \"23850191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SETD7 balances chromatin-relaxing versus signaling roles in vivo unclear\", \"Upstream signals directing YAP methylation not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed SETD7 roles in DNA-damage chromatin responses and TGF-β/fibrosis control by methylating ARTD1/PARP1 and Smad7, with the latter coupling methylation to Arkadia-dependent degradation in vivo.\",\n      \"evidence\": \"In vitro methylation, laser-induced damage recruitment imaging, ubiquitination assays, and a Set9 knockout lung-fibrosis mouse model\",\n      \"pmids\": [\"24088713\", \"27292644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct contribution of ARTD1 methylation to repair outcomes not quantified\", \"Pharmacological translation of the fibrosis finding untested in the timeline\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Delivered a potent selective chemical probe ((R)-PFI-2) that occupies the substrate groove and phenocopies genetic loss, enabling acute interrogation of SETD7 function.\",\n      \"evidence\": \"Ki determination, crystallography of the inhibitor complex, chemoproteomics, and cell-based YAP localization assays\",\n      \"pmids\": [\"25136132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Probe does not distinguish individual substrate contributions\", \"Off-target methyltransferase activity in complex tissues not exhaustively excluded\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Implicated SETD7 in cell-cycle and survival transcription programs through E2F1 coactivation and a proposed Mdm2 interaction, linking it to genotoxic stress responses.\",\n      \"evidence\": \"Co-IP, ChIP, gene expression and G1/S progression assays across cancer cell lines\",\n      \"pmids\": [\"25124555\", \"26317544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mdm2 regulation rests on a single low-confidence Co-IP/correlation study without mechanistic depth\", \"Direct versus indirect histone effects at E2F1 promoters not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Expanded SETD7 control to metabolic, hypoxic, and developmental transcription factors (Pdx1, HIF-1α/2α, Gli3, β-catenin) with marks driving either activation, repression, or GSK-3β-coupled degradation.\",\n      \"evidence\": \"In vitro methylation with MS/mutagenesis, ChIP at HREs, half-life assays, and conditional/whole-body knockout phenotypes\",\n      \"pmids\": [\"25713082\", \"25897119\", \"27146893\", \"26116705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why the same enzyme activates some factors and degrades others remains mechanistically unexplained\", \"Tissue specificity of these competing outcomes not systematically tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Integrated SETD7 into Wnt-Hippo crosstalk and additional transcription-factor regulation, showing YAP methylation gates β-catenin nuclear accumulation and tumorigenesis while YY1 methylation tunes its DNA binding.\",\n      \"evidence\": \"SETD7 knockout intestinal tumor/regeneration model, YAP-AXIN1-β-catenin complex Co-IP, EMSA, and ChIP\",\n      \"pmids\": [\"27046831\", \"26902152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of the YAP-AXIN1-β-catenin-SETD7 complex unresolved\", \"YY1 regulation from a single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established a catalysis-independent reader function and additional stability control, with SETD7 binding H3K36me to drive cardiac differentiation and methylating SOX2 within a writer-eraser-reader module.\",\n      \"evidence\": \"ChIP-seq, Co-IP with SWI/SNF and NKX2.5, enzyme-dead mutant analysis, and SOX2 stability assays with LSD1/PHF20L1 knockdown\",\n      \"pmids\": [\"29499155\", \"29358331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of H3K36me reading not defined\", \"Generality of the catalysis-independent role beyond cardiac lineage untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified Rpl29 K5 as a SETD7-exclusive mark and a cellular biomarker of enzyme activity, providing a tool to monitor inhibition.\",\n      \"evidence\": \"In vitro methylation, methylation-specific antibody, subcellular fractionation, and (R)-PFI-2 response\",\n      \"pmids\": [\"29959229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Rpl29 methylation limited to localization, with no effect on translation\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined how SETD7 activity is positioned and the breadth of its DNA-repair and chromatin roles, showing SENP3 deSUMOylation recruits it to muscle gene loci and that it methylates UHRF1 to promote homologous recombination.\",\n      \"evidence\": \"Co-IP, deSUMOylation and polyubiquitination assays, ChIP, phosphorylation-mutant analysis, and HR assays\",\n      \"pmids\": [\"31141694\", \"30357346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How SUMOylation status mechanistically gates SETD7 catalysis unclear\", \"UHRF1-PCNA repair axis from a single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed SETD7 regulates mitosis directly by dimethylating PLK1 to dampen kinase activity at kinetochores, expanding its reach beyond transcription.\",\n      \"evidence\": \"In vitro methylation, K191 mutagenesis, kinase activity assays, and kinetochore-microtubule attachment/mitosis assays with inhibitor\",\n      \"pmids\": [\"31863092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"This is a dimethylation event, atypical for the canonical mono-methylase, and structural basis is unexplained\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified TRIM21 as a proteasomal negative regulator of SETD7, defining how the enzyme's own abundance is controlled in cancer contexts.\",\n      \"evidence\": \"Mass spectrometry, Co-IP, GST pulldown, ubiquitination assays, and ChIP-seq with xenograft analysis\",\n      \"pmids\": [\"32102992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals triggering TRIM21-mediated SETD7 degradation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked SETD7 to neurodegeneration-associated Tau modification, with methylation at K132 priming K130 and correlating with pathology stage.\",\n      \"evidence\": \"Mass spectrometry in human AD brain, methylation-specific antibodies, knockdown/inhibitor studies, and subcellular fractionation\",\n      \"pmids\": [\"34215303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution of Tau methylation to pathology not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated a translational cardioprotective role, with SETD7-mediated YAP methylation impairing antioxidant gene expression during energy deprivation and (R)-PFI-2 preventing ischemia/reperfusion injury.\",\n      \"evidence\": \"Cardiomyocyte energy-deprivation culture, SETD7 knockout I/R mouse model, pharmacological inhibition, and YAP localization/mtROS readouts\",\n      \"pmids\": [\"35709329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether benefit derives solely from YAP versus other cardiac substrates not isolated\", \"Long-term safety of SETD7 inhibition not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what governs whether a given SETD7 methylation event stabilizes versus degrades a substrate, or activates versus represses transcription, and how catalytic versus reader functions are partitioned across tissues.\",\n      \"evidence\": \"No single study in the timeline reconciles the opposing functional outcomes of SETD7 methylation across its many substrates\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying rule predicting activating versus degradative outcomes\", \"Endogenous substrate priority and stoichiometry largely unquantified\", \"Reader (H3K36me) versus writer contributions separated only in cardiac differentiation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 5, 8, 9, 11, 18, 29]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 5, 8, 9, 11, 18, 29, 37]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 20, 32]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 36, 40]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 8, 30, 32]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [17, 39]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 5, 11, 19, 28]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 22, 26, 27, 29, 30, 39]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [18, 21, 35]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [25, 37]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [14, 17, 28, 32]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8, 9, 29, 33]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"complexes\": [\"YAP-AXIN1-β-catenin complex\"],\n    \"partners\": [\"YAP1\", \"DNMT1\", \"RELA\", \"SUV39H1\", \"MyoD\", \"SIRT1\", \"SENP3\", \"TRIM21\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}