{"gene":"SETD7","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2002,"finding":"Crystal structure of human SET7/9 reveals a N-terminal beta-sheet domain and conserved SET domain; mutagenesis identified two C-terminal residues essential for catalytic activity toward H3K4; AdoMet cofactor binding mode and role of invariant residues in catalysis, substrate binding, and AdoMet binding were established.","method":"Crystal structure + site-directed mutagenesis + biochemical assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis and biochemical validation in a single study","pmids":["12372304"],"is_preprint":false},{"year":2003,"finding":"High-resolution crystal structure of ternary complex of human SET7/9 with histone H3K4 peptide and AdoMet cofactor shows the peptide and cofactor bind on opposite enzyme surfaces; the target lysine side chain inserts into a narrow channel connecting the two surfaces to access the active site; SET7/9 is exclusively a mono-methylase due to structural constraints.","method":"Crystal structure of ternary complex + solution studies","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — high-resolution ternary complex structure with biochemical validation, replicated across labs","pmids":["12540855"],"is_preprint":false},{"year":2003,"finding":"Crystal structures of SET7/9 in complex with AdoMet reveal the active site architecture: a binding pocket between the SET domain and c-SET helix for AdoMet in an unusual conformation, a narrow substrate-specific channel permitting only unmethylated lysines, and a catalytic tyrosine residue; SET7/9 can transfer two but not three methyl groups to unmodified H3K4 without substrate dissociation.","method":"Crystal structure (1.7 Å and 2.3 Å) + biochemical assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — high-resolution structures with biochemical validation","pmids":["12514135"],"is_preprint":false},{"year":2004,"finding":"SET7/9 (SET9) monomethylates the TBP-associated factor TAF10 at a single lysine in the loop 2 region of its histone-fold domain; methylated TAF10 has increased affinity for RNA polymerase II, linking this modification to preinitiation complex formation; SET9-mediated TAF10 methylation potentiates transcription of a subset of TAF10-dependent genes.","method":"In vitro methylation assay, reporter assays, TAF10-null cell complementation with methylation-deficient mutant, Co-IP","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro methylation plus genetic rescue with methylation-deficient mutant and functional readouts","pmids":["15099517"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of Pr-Set7 (Set8) ternary complex shows it is exclusively a mono-methylase for H4K20; a histidine residue within the substrate near the target lysine is required for active site completion; the highly variable component of the SET domain governs interactions with the target histone peptide and ensures nucleosome specificity.","method":"Crystal structure + NMR + biochemical assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus NMR and biochemical validation","pmids":["15933069"],"is_preprint":false},{"year":2006,"finding":"SET7/9 recognizes a conserved K/R-S/T/A motif preceding the target lysine and has a propensity to bind aspartates/asparagines C-terminal to the target; this consensus motif was used to identify novel substrates including TAF7 (methylated at K5 in vitro).","method":"Crystal structure with TAF10 peptide + mutagenesis + in vitro methylation assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — structural analysis with mutagenesis and in vitro biochemistry","pmids":["16415881"],"is_preprint":false},{"year":2006,"finding":"Ab initio QM/MM-FE calculations demonstrate that SET7/9-catalyzed methyl transfer is a typical in-line SN2 nucleophilic substitution reaction with ~70% dissociative character; product specificity as a monomethyltransferase is achieved by disrupting near-attack conformations for the dimethylation reaction.","method":"Ab initio QM/MM free energy calculations + molecular dynamics simulations","journal":"Journal of the American Chemical Society","confidence":"Medium","confidence_rationale":"Tier 1 computational — consistent with experimental rate constant but no direct mutagenesis","pmids":["16433545"],"is_preprint":false},{"year":2008,"finding":"SET7 directly methylates estrogen receptor alpha (ERα) at lysine 302 (K302); this monomethylation stabilizes ERα and is required for efficient ER recruitment to target gene promoters and transactivation; a breast cancer-associated mutation K303R alters K302 methylation in vitro and in vivo. Crystal structure of the SET7-ER peptide complex reveals the molecular basis for substrate recognition.","method":"In vitro methylation, crystal structure, ChIP, transactivation assays, cancer mutation analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro methylation, structural data, and multiple cellular functional assays in a single study","pmids":["18471979"],"is_preprint":false},{"year":2008,"finding":"SET7/9 functions as a coactivator of NF-κB: it is recruited to NF-κB-regulated inflammatory gene promoters in response to TNF-α, and its gene silencing reduces H3K4 monomethylation at these promoters and decreases NF-κB p65 recruitment, suppressing inflammatory gene induction.","method":"siRNA knockdown, ChIP, gene expression analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP and knockdown with defined chromatin and transcriptional phenotypes, single lab","pmids":["18650421"],"is_preprint":false},{"year":2008,"finding":"Set7/9-mediated monomethylation of p53 at K369 (mouse; K372 in human) is required for subsequent Tip60 acetyltransferase binding to p53 and p53 acetylation; Set7/9 null mouse cells fail to methylate p53, cannot induce p53 downstream targets upon DNA damage, and are predisposed to oncogenic transformation.","method":"Set7/9 knockout mouse model, in vivo methylation assay, Co-IP, gene expression analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — genetic null mouse with multiple orthogonal readouts linking methylation to acetylation and downstream function","pmids":["18280244"],"is_preprint":false},{"year":2008,"finding":"Set7/9 is required in pancreatic islet beta-cells for normal expression of glucose-stimulated insulin secretion genes (Ins1/2, Glut2, MafA); its depletion causes loss of H3K4 dimethylation and RNA polymerase II recruitment at insulin gene promoters, and impairs glucose-stimulated insulin secretion.","method":"siRNA knockdown in insulinoma cells and primary mouse islets, ChIP, Ca2+ mobilization assay, insulin secretion assay","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and functional physiological assays but single lab","pmids":["18984737"],"is_preprint":false},{"year":2009,"finding":"SET7 colocalizes and directly interacts with DNMT1 and specifically monomethylates DNMT1 at Lys-142; methylated DNMT1 peaks during S and G2 phases and is prone to proteasome-mediated degradation; SET7 overexpression decreases DNMT1 levels and siRNA knockdown stabilizes DNMT1.","method":"Co-localization, direct interaction (pulldown), in vitro methylation, cell cycle analysis, proteasome inhibition, siRNA/OE","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including direct methylation, co-localization, and gain/loss-of-function with defined stability phenotype","pmids":["19282482"],"is_preprint":false},{"year":2009,"finding":"Set9 (SETD7) physically associates with the RelA subunit of NF-κB in vitro and in vivo; it monomethylates RelA at K314 and K315; this methylation induces proteasome-mediated degradation of promoter-associated RelA, thereby inhibiting NF-κB action; depletion of Set9 or mutation of methylation sites prolongs NF-κB DNA binding and enhances TNF-α-induced target gene expression.","method":"Co-IP, GST pulldown, mass spectrometry, in vitro methylation, proteasome inhibition, siRNA knockdown, mutagenesis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — direct identification of methylation sites by MS, mutagenesis, and multiple functional assays","pmids":["19262565"],"is_preprint":false},{"year":2010,"finding":"Set7/9 (KMT7) monomethylates the HIV Tat protein at lysine 51 located in the RNA-binding domain; Set7/9 itself binds TAR RNA and associates with Tat/P-TEFb complexes at the HIV promoter; knockdown of Set7/9 suppresses Tat transactivation while methylation-deficient Tat (K51A) is unaffected, demonstrating methylation-dependent coactivation of HIV transcription.","method":"In vitro methylation, RNA binding assay, ChIP, siRNA knockdown, transactivation assays","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro methylation confirmed at specific site, RNA binding, ChIP, and genetic control (K51A mutant)","pmids":["20227666"],"is_preprint":false},{"year":2010,"finding":"The androgen receptor (AR) directly interacts with and is methylated at lysine 632 by SET9 (SETD7); this methylation enhances AR transcriptional activity by facilitating N-C terminal interdomain communication and recruitment to androgen-target gene promoters.","method":"Co-IP, in vitro methylation, mutagenesis (K632A), ChIP, transactivation assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 — direct methylation demonstrated, site confirmed by mutagenesis, multiple functional readouts","pmids":["20959290"],"is_preprint":false},{"year":2011,"finding":"Set7/9 interacts with SIRT1 both in vitro and in vivo; upon DNA damage, enhanced Set7/9-SIRT1 interaction suppresses SIRT1-p53 interaction, abrogating SIRT1-mediated p53 deacetylation and increasing p53 transcriptional activity; this is partially independent of SIRT1 methylation by Set7/9.","method":"Co-IP, in vitro binding, in vitro methylation, reporter assays, DNA damage response analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal Co-IP and functional assays, but mechanism partially indirect","pmids":["21245319"],"is_preprint":false},{"year":2011,"finding":"In Set7/9-deficient mice (independent knockout strain), p53-dependent transcription and tumor suppression are normal after genotoxic and oncogenic stress, indicating that Set7/9-mediated p53 methylation at K372 is not a major regulatory event for p53 activity in vivo.","method":"Independent Set7/9 knockout mouse model, gene expression analysis, oncogenic stress assays","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 — independent genetic null mouse contradicts prior report; single lab but rigorous in vivo epistasis","pmids":["21855805"],"is_preprint":false},{"year":2011,"finding":"Set7 directly interacts with MyoD and promotes myoblast differentiation; Set7 knockdown or dominant-negative expression impairs skeletal muscle differentiation and myofibril assembly, reduces H3K4me1, and decreases expression of myocyte enhancer factor 2 and contractile protein genes; Set7 also precludes Suv39h1-mediated H3K9 methylation on myogenic gene promoters.","method":"siRNA/dominant-negative expression, Co-IP, ChIP, differentiation assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and ChIP with multiple functional differentiation readouts, single lab","pmids":["21859860"],"is_preprint":false},{"year":2011,"finding":"Set9 methyltransferase directly methylates FoxO3 at lysine 271 in vitro and in cells; methylation by Set9 decreases FoxO3 protein stability while moderately increasing its transcriptional activity.","method":"In vitro methylation, tandem mass spectrometry, methyl-specific antibodies, stability assays, transcriptional reporter assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro methylation with MS site identification and cellular functional assays, single lab","pmids":["22820736"],"is_preprint":false},{"year":2011,"finding":"Peptide array methylation analysis determined an optimized target sequence for SET7/9, identifying 91 new peptide substrates from human proteins; nine non-histone proteins (AKA6, CENPC1, MeCP2, MINT, PPARBP, ZDH8, Cullin1, IRF1, TTK) and H2A/H2B were confirmed as SET7/9 substrates in vitro and in vivo; phosphorylation of substrate proteins inhibits SET7/9; SET7/9 can dimethylate MINT lysine in vitro and in vivo.","method":"Peptide array methylation, in vitro and in vivo methylation confirmation, mass spectrometry","journal":"Chemistry & biology","confidence":"Medium","confidence_rationale":"Tier 2 — systematic substrate identification with in vitro and in vivo confirmation","pmids":["21276944"],"is_preprint":false},{"year":2012,"finding":"Set7/9 directly methylates the FXR nuclear receptor at lysine 206 in vitro and in vivo; this methylation enhances FXR/RXRα binding to the FXR response element and is required for transcriptional activation of FXR target genes (SHP, BSEP); Set7/9 occupies the FXRE chromatin in vivo.","method":"In vitro methylation, mutagenesis (K206R), Co-IP, GST pulldown, mammalian two-hybrid, EMSA, ChIP, reporter assays","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 1-2 — methylation site confirmed by mutagenesis with multiple complementary methods and functional readouts","pmids":["22345554"],"is_preprint":false},{"year":2013,"finding":"SET7/9 methylates the RelA/NF-κB-associated histone methyltransferase SUV39H1 at K105 and K123 in response to DNA damage; this methylation markedly reduces SUV39H1 methyltransferase activity, leading to decreased H3K9me3 in heterochromatin, satellite repeat derepression (heterochromatin relaxation), and genome instability.","method":"Co-IP, GST pulldown, Western blot with methyl-specific antibodies, mass spectrometry, MNase sensitivity assay, immunofluorescence","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — methylation sites identified by MS, enzyme activity assayed, and downstream chromatin consequences measured","pmids":["23509280"],"is_preprint":false},{"year":2013,"finding":"SET7/9 methylates histone H1.4 at multiple lysines (K121, K129, K159, K171, K177, K192) in the C-terminal KAK motifs; ADP-ribosylation of H3 by ARTD1 prevents H3 methylation by SET7/9 but allows subsequent H1 methylation; H1 and H3 compete with each other for SET7/9-dependent methylation.","method":"In vitro methylation with isolated histones, PAR-ylation assays, site mapping","journal":"Epigenetics & chromatin","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro biochemical demonstration with site identification, single lab","pmids":["23289424"],"is_preprint":false},{"year":2013,"finding":"SETD7 monomethylates YAP at K494; this methylation is critical for cytoplasmic retention of YAP; Set7-null mice have a larger intestinal progenitor compartment coinciding with increased YAP target gene expression, demonstrating in vivo regulation of the Hippo pathway by Set7-dependent YAP methylation.","method":"Set7 knockout mice, in vitro methylation, subcellular fractionation, intestinal progenitor analysis, gene expression","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model with specific methylation site identified and mechanistic link to YAP localization established","pmids":["23850191"],"is_preprint":false},{"year":2013,"finding":"SET7/9 methylates ARTD1 (PARP1) at K508 in vitro and in vivo; ARTD1 methylation by SET7/9 enhances poly-ADP-ribose synthesis upon oxidative stress and promotes ARTD1 recruitment to DNA damage sites in a SET7/9-dependent manner; ARTD1 auto-modification inhibits its methylation by SET7/9.","method":"In vitro methylation, in vivo methylation (methyl-specific antibody), laser irradiation, PAR formation assay","journal":"Open biology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo methylation confirmed, functional PAR assay performed, single lab","pmids":["24088713"],"is_preprint":false},{"year":2013,"finding":"SET7/9 negatively regulates the antiviral restriction factor IFITM3 by monomethylating it at K88; viral infection (VSV, influenza A) promotes IFITM3-SET7 interaction to increase IFITM3-K88me1 and reduce antiviral activity; IFN-α reduces IFITM3-K88me1 levels.","method":"In vitro and in vivo methylation, viral infection assays, Co-IP, methyl-specific antibody","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct methylation shown with functional viral restriction readout, single lab","pmids":["24129573"],"is_preprint":false},{"year":2014,"finding":"(R)-PFI-2 is a potent (Ki ~0.33 nM), selective, cell-active inhibitor of SETD7 that occupies the substrate peptide binding groove in a cofactor-dependent, substrate-competitive manner, making direct contact with the AdoMet methyl group; in cells, it phenocopies Setd7 deficiency by modulating YAP localization and Hippo pathway signaling.","method":"Biochemical inhibition assay, X-ray crystallography, chemoproteomics, cell-based YAP localization assay, MEF Setd7-null comparison","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structure of inhibitor-enzyme complex, biochemical Ki measurement, and cellular target engagement validated","pmids":["25136132"],"is_preprint":false},{"year":2015,"finding":"Set7 methylates HIF-1α at K32 and HIF-2α at K29; this methylation inhibits HIF-α transcriptional activity by impairing HIF-α occupancy at hypoxia response elements; Set7-null fibroblasts show upregulated HIF target genes and increased glucose uptake/ATP levels under hypoxia.","method":"In vitro methylation, Set7-null fibroblasts, shRNA knockdown, ChIP, metabolic assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro methylation with in vivo genetic null and functional metabolic phenotype, single lab","pmids":["25897119"],"is_preprint":false},{"year":2015,"finding":"SET7/9 interacts with and methylates β-catenin at K180 in vitro and in vivo; methylated β-catenin is recognized by GSK-3β for degradation; non-methylatable β-catenin (K180R) has a longer half-life; SET7/9 knockdown or K180R mutation enhances Wnt/β-catenin target gene expression and cancer cell growth.","method":"Co-IP, in vitro methylation, mass spectrometry, mutagenesis, stability assays, gene expression","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1-2 — methylation site confirmed by MS and mutagenesis, downstream degradation mechanism defined, multiple functional assays","pmids":["26116705"],"is_preprint":false},{"year":2015,"finding":"Set7/9 methylates the androgen receptor at K630; alanine substitution prevents methylation in vitro and in vivo; Set7 overexpression potentiates AR-mediated transactivation while depletion inhibits AR activity; methylation promotes AR N-C terminal interaction and co-occupies androgen response elements with activated histone marks.","method":"In vitro methylation, mutagenesis (K630A), Co-IP, ChIP, transactivation assays","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — direct methylation, mutagenesis, and multiple functional readouts, single lab; corroborates earlier finding at adjacent K632","pmids":["21273441"],"is_preprint":false},{"year":2015,"finding":"KMT Set7/9 physically interacts with Mdm2 and regulates its expression; several cancer cell lines with inverse expression of Set7/9 and Mdm2 show altered sensitivity to genotoxic stress, placing Set7/9 upstream of Mdm2 in the DNA damage response.","method":"Co-IP, gene expression, siRNA, cell viability assays, bioinformatics","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP and expression analysis without direct mechanistic reconstitution","pmids":["26317544"],"is_preprint":false},{"year":2015,"finding":"Set7/9 methylates Pdx1 at K123 and K131; K131 methylation (but not K123) is required for Set7/9-mediated augmentation of Pdx1 transcriptional activity; conditional beta-cell-specific Set7 knockout mice exhibit glucose intolerance and impaired glucose-stimulated insulin secretion with reduced Pdx1 target gene expression.","method":"Mass spectrometry, mutagenesis, Co-IP, reporter assays, conditional knockout mouse, glucose tolerance test","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — MS identification of methylation sites, mutagenesis, conditional KO with physiological phenotype","pmids":["25713082"],"is_preprint":false},{"year":2016,"finding":"SETD7 is part of a complex containing YAP, AXIN1, and β-catenin; SETD7-dependent methylation of YAP facilitates Wnt-induced nuclear accumulation of β-catenin; SETD7 is required for Wnt-driven intestinal tumorigenesis and regeneration, mechanistically linking the Hippo/YAP and Wnt/β-catenin pathways.","method":"Co-IP, SETD7 KO mouse intestinal tumorigenesis model, β-catenin nuclear fractionation, gene expression","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model plus complex identification and defined molecular mechanism linking two pathways","pmids":["27046831"],"is_preprint":false},{"year":2016,"finding":"Set9 methyltransferase promotes TGF-β signaling by methylating the inhibitory Smad7, which promotes Smad7 interaction with the E3 ligase Arkadia and subsequent ubiquitination-dependent degradation of Smad7; Set9-deficient mice show elevated Smad7 levels and are protected from bleomycin- and Ad-TGF-β-induced pulmonary fibrosis.","method":"In vitro methylation, Co-IP, ubiquitination assay, Set9-KO mouse fibrosis models","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — direct methylation, interaction with E3 ligase, and in vivo genetic validation in two fibrosis models","pmids":["27292644"],"is_preprint":false},{"year":2016,"finding":"Set7 methylates Gli3 (full-length form) at K436 and K595; methylation at K436 increases Gli3 stability and at K595 increases its DNA-binding ability, resulting in enhanced Shh signaling activation; Gli3 methylation contributes to tumor growth and metastasis in non-small cell lung cancer.","method":"In vitro methylation, mutagenesis, stability assays, DNA-binding assays, in vitro/in vivo tumor models","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro methylation with mutagenesis, functional phenotypes in vitro and in vivo, single lab","pmids":["27146893"],"is_preprint":false},{"year":2016,"finding":"SET7/9 methylates YY1 transcription factor at K173 and K411; this methylation regulates YY1 DNA-binding activity both in vitro and at specific genomic loci in cells and is involved in YY1-regulated gene transcription and cell proliferation.","method":"In vitro methylation, mutagenesis, EMSA, ChIP, reporter assays, cell proliferation assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct methylation with mutagenesis and functional readouts, single lab","pmids":["26902152"],"is_preprint":false},{"year":2016,"finding":"An asparagine residue in SET7/9 that mediates AdoMet sulfur-oxygen chalcogen bonding enhances AdoMet binding affinity over the product AdoHcy; structural, biochemical, and computational analyses show that S···O chalcogen bonds contribute to AdoMet recognition and enable substrate-product discrimination.","method":"X-ray crystallography, mutagenesis, biochemical binding assays, quantum mechanical calculations","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis and computational corroboration","pmids":["26713889"],"is_preprint":false},{"year":2018,"finding":"Rpl29 (ribosomal protein L29) is a major substrate of Set7/9; Rpl29 K5 is methylated exclusively by Set7/9 and can be demethylated by Lsd1; Rpl29 K5 methylation affects Rpl29 subcellular localization but not global protein synthesis; Rpl29 K5 methylation serves as a reliable cellular biomarker for Set7/9 activity validated by (R)-PFI-2 treatment.","method":"In vitro methylation, methyl-specific antibody, siRNA, subcellular fractionation, inhibitor treatment (R)-PFI-2","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — exclusive substrate identification with writer/eraser confirmed, functional localization phenotype, inhibitor validation","pmids":["29959229"],"is_preprint":false},{"year":2018,"finding":"Setd7 facilitates the transition from activated, proliferating myogenic stem cells (MuSCs) to differentiation-primed progenitors by regulating nuclear accumulation of β-catenin; genetic or pharmacological inhibition of Setd7 promotes in vitro MuSC expansion and enhances engraftment and therapeutic potential upon transplantation.","method":"Genetic Setd7 deletion, pharmacological inhibition (R)-PFI-2, β-catenin nuclear fractionation, transplantation assays, muscular dystrophy preclinical model","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological KO with mechanistic β-catenin readout and in vivo therapeutic validation","pmids":["29395054"],"is_preprint":false},{"year":2019,"finding":"UHRF1 is methylated by SET7 and demethylated by LSD1; DNA damage induces UHRF1 methylation, and UHRF1 phosphorylation in S phase is a prerequisite for its interaction with SET7; UHRF1 methylation promotes polyubiquitin chain conjugation to PCNA and facilitates homologous recombination for DNA double-strand break repair; SET7-mediated UHRF1 methylation is essential for cell viability against DNA damage.","method":"In vitro methylation, Co-IP, ubiquitination assay, siRNA, homologous recombination reporter assay, cell viability assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — direct methylation and functional DNA repair readouts, single lab","pmids":["30357346"],"is_preprint":false},{"year":2019,"finding":"The SUMO-specific isopeptidase SENP3 associates with SETD7 and deSUMOylates it; by recruiting deSUMOylated SETD7 to the MyHC-II gene locus, SENP3 promotes SETD7 association with active RNA Pol II and precludes Suv39h1; SENP3 is degraded in cachexia, impairing SETD7-dependent MyHC-II expression and sarcomere organization.","method":"Co-IP, deSUMOylation assay, ChIP, siRNA knockdown, sarcomere morphology analysis, muscle contractility assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — molecular mechanism defined by multiple biochemical and cell biological approaches, single lab","pmids":["31141694"],"is_preprint":false},{"year":2020,"finding":"SET7/9 dimethylates PLK1 at K191 during early mitosis, reducing PLK1 kinase activity by limiting ATP utilization; overexpression of non-methylatable PLK1 (K191R) or chemical inhibition of SET7/9 causes mitotic arrest due to destabilized kinetochore-microtubule attachments, revealing methylation-dependent regulation of accurate chromosome segregation.","method":"In vitro methylation, mutagenesis (K191R), kinase assays, mitotic arrest analysis, SET7/9 inhibitor treatment","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct methylation with mutagenesis and kinase activity assay, functional mitotic phenotype, single lab","pmids":["31863092"],"is_preprint":false},{"year":2020,"finding":"TRIM21 physically associates with SET7/9 and functions as a major negative regulator upstream of SET7/9 through a proteasome-dependent ubiquitination mechanism; SET7/9 promotes breast cancer cell proliferation, migration, and invasion via activation of RUNX2.","method":"Co-IP, GST pulldown, ubiquitination assay, ChIP-seq, cell proliferation/migration/invasion assays, xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct TRIM21-SET7/9 interaction with ubiquitination mechanism and functional cancer phenotypes","pmids":["32102992"],"is_preprint":false},{"year":2023,"finding":"SETD7 is activated upon energy deprivation in cardiomyocytes and methylates YAP, leading to YAP cytosolic retention and impaired transcription of antioxidant genes MnSOD and CAT; this drives mitochondrial ROS accumulation, organelle swelling, and apoptosis; pharmacological SETD7 inhibition with (R)-PFI-2 or genetic SETD7 deletion restores YAP nuclear localization and MnSOD/CAT expression, attenuating myocardial ischemia/reperfusion injury.","method":"SETD7 KO mouse I/R model, (R)-PFI-2 treatment, YAP nuclear fractionation, ROS measurement, mitochondrial morphology, Ca2+-activated tension, NRVMs, human ICM LV samples","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 — genetic KO and pharmacological inhibition with mechanistic YAP methylation-localization link and multiple orthogonal readouts, confirmed in human tissue","pmids":["35709329"],"is_preprint":false}],"current_model":"SETD7 (SET7/9) is a lysine monomethyltransferase that uses a narrow substrate-binding channel and an SN2 catalytic mechanism to transfer a single methyl group from AdoMet to histone H3K4 and a broad spectrum of non-histone substrates—including p53, ERα, DNMT1, NF-κB RelA, YAP, β-catenin, UHRF1, PLK1, Smad7, TAF10, AR, FXR, HIF-1α/2α, and others—thereby regulating substrate stability, subcellular localization, protein-protein interactions, and transcriptional activity in pathways controlling inflammation, DNA damage response, Hippo/Wnt signaling, cell cycle progression, and differentiation."},"narrative":{"teleology":[{"year":2002,"claim":"Determining the three-dimensional architecture of SET7/9 established how the N-terminal β-sheet and conserved SET domain organize the catalytic center around AdoMet, and identified two C-terminal residues essential for H3K4 methylation.","evidence":"Crystal structure with site-directed mutagenesis and biochemical assays on recombinant human SET7/9","pmids":["12372304"],"confidence":"High","gaps":["No substrate peptide in the structure; substrate-binding mode unknown","Product specificity (mono- vs. di- vs. tri-methyl) not yet explained"]},{"year":2003,"claim":"Ternary complex structures resolved how the target lysine threads through a narrow channel between cofactor and substrate binding surfaces, explaining SET7/9's exclusive monomethyltransferase activity and the structural basis for substrate specificity.","evidence":"High-resolution crystal structures of SET7/9–H3K4 peptide–AdoMet ternary complex plus solution studies","pmids":["12540855","12514135"],"confidence":"High","gaps":["Whether channel geometry permits any dimethylation in special contexts was debated","Non-histone substrate recognition not yet addressed"]},{"year":2004,"claim":"The discovery that SET7/9 monomethylates the non-histone protein TAF10, enhancing its affinity for RNA Pol II and potentiating transcription, established the precedent that SET7/9 functions beyond histone modification.","evidence":"In vitro methylation of TAF10, reporter assays, and genetic rescue with methylation-deficient TAF10 mutant in TAF10-null cells","pmids":["15099517"],"confidence":"High","gaps":["Physiological importance in vivo not tested","Whether other TAF subunits are substrates was unclear"]},{"year":2006,"claim":"Definition of a conserved K/R-S/T/A substrate recognition motif, together with QM/MM-computed SN2 catalytic mechanism, provided predictive rules for new substrate identification and explained product specificity at the quantum-mechanical level.","evidence":"Crystal structure with TAF10 peptide, mutagenesis, peptide methylation assays, and ab initio QM/MM free energy calculations","pmids":["16415881","16433545"],"confidence":"High","gaps":["Motif-based prediction not yet validated proteome-wide","Computational mechanism awaited experimental kinetic isotope effect confirmation"]},{"year":2008,"claim":"Multiple studies revealed that SET7/9 methylates diverse transcription factors and signaling proteins—ERα (K302, stabilization), p53 (K372, enabling Tip60 acetylation and DNA damage response), and NF-κB-target promoters (H3K4me1 deposition)—establishing it as a broad-spectrum signaling methyltransferase.","evidence":"Crystal structure of SET7–ERα peptide complex, Set7/9 knockout mouse p53 methylation studies, and ChIP/siRNA in TNF-α-stimulated cells","pmids":["18471979","18280244","18650421"],"confidence":"High","gaps":["Relative importance of histone vs. non-histone methylation at each locus unclear","An independent KO later questioned in vivo p53 dependence on Set7/9"]},{"year":2009,"claim":"Identification of DNMT1-K142 and RelA-K314/K315 as SET7/9 substrates whose methylation triggers proteasomal degradation established a recurring mechanism: methylation marks proteins for destruction.","evidence":"Direct in vitro methylation, mass spectrometry, proteasome inhibitor rescue, siRNA and overexpression in human cells","pmids":["19282482","19262565"],"confidence":"High","gaps":["The E3 ligase(s) recognizing methyl-DNMT1 were unknown","Whether RelA methylation-degradation operates in all NF-κB-dependent contexts was untested"]},{"year":2011,"claim":"An independent Set7/9-null mouse showed normal p53-dependent transcription and tumor suppression after genotoxic and oncogenic stress, challenging the earlier model that Set7/9-mediated p53-K372 methylation is essential for the DNA damage response in vivo.","evidence":"Independent Set7/9 knockout mouse, gene expression analysis, oncogenic stress assays","pmids":["21855805"],"confidence":"Medium","gaps":["Discrepancy with the earlier KO study not fully resolved—may reflect strain or context differences","Whether Set7/9 has redundant or compensated roles in p53 activation in specific tissues remains open"]},{"year":2011,"claim":"Systematic peptide array screening expanded the validated substrate repertoire to dozens of proteins (including MeCP2, Cullin1, IRF1, histones H2A/H2B, H1.4) and demonstrated that substrate phosphorylation inhibits SET7/9, revealing crosstalk between modification pathways.","evidence":"Peptide array methylation, in vitro and in vivo confirmation by mass spectrometry","pmids":["21276944","23289424"],"confidence":"Medium","gaps":["Many array-identified substrates lack in vivo functional validation","Stoichiometry and biological significance of most new substrates unknown"]},{"year":2013,"claim":"Discovery that SETD7 monomethylates YAP at K494 to enforce its cytoplasmic retention, with Set7-null mice showing expanded intestinal progenitors and elevated YAP target genes, established SETD7 as a Hippo pathway regulator in vivo.","evidence":"Set7 knockout mice, in vitro methylation, subcellular fractionation, intestinal progenitor cell analysis","pmids":["23850191"],"confidence":"High","gaps":["The cytoplasmic reader recognizing methyl-YAP was not identified","Whether YAP methylation is dynamically reversed by a demethylase was unknown"]},{"year":2015,"claim":"Methylation of β-catenin at K180 by SET7/9, promoting GSK-3β-dependent degradation, together with methylation of Pdx1 activating insulin gene expression in β-cells, expanded the in vivo roles of SETD7 to Wnt signaling and glucose homeostasis.","evidence":"Mass spectrometry site identification, mutagenesis (K180R), conditional β-cell KO mouse with glucose intolerance phenotype","pmids":["26116705","25713082"],"confidence":"High","gaps":["Whether β-catenin K180 methylation cooperates with YAP methylation in intestinal tumorigenesis was unknown","The demethylase counteracting β-catenin methylation was not identified"]},{"year":2016,"claim":"SETD7 was shown to integrate Hippo and Wnt pathways: it exists in a complex with YAP, AXIN1, and β-catenin, and is required for Wnt-driven intestinal tumorigenesis and regeneration, while also methylating Smad7 to promote TGF-β signaling via Arkadia-mediated degradation.","evidence":"SETD7 KO intestinal tumorigenesis model, Co-IP of quaternary complex, Set9-KO pulmonary fibrosis models","pmids":["27046831","27292644"],"confidence":"High","gaps":["How SETD7 is dynamically recruited to the AXIN1 destruction complex is unclear","Whether the Smad7 methylation-degradation axis operates in all TGF-β contexts is untested"]},{"year":2018,"claim":"Identification of Rpl29-K5 as a major and exclusive SET7/9 substrate reversible by LSD1 provided a reliable cellular biomarker for SETD7 activity, validated with the selective chemical probe (R)-PFI-2.","evidence":"In vitro methylation, methyl-specific antibody, (R)-PFI-2 inhibitor treatment, subcellular fractionation","pmids":["29959229"],"confidence":"Medium","gaps":["Functional consequence of Rpl29 methylation beyond localization change is unknown","Whether Rpl29 methylation affects ribosome biogenesis or translation of specific mRNAs was not addressed"]},{"year":2019,"claim":"SET7-mediated methylation of UHRF1, dependent on prior S-phase phosphorylation, promotes PCNA polyubiquitination and homologous recombination repair, placing SETD7 directly in the DNA double-strand break repair pathway.","evidence":"In vitro methylation, Co-IP, HR reporter assay, siRNA, cell viability after DNA damage","pmids":["30357346"],"confidence":"Medium","gaps":["The specific UHRF1 methylation site was not mapped by mutagenesis","Independent replication in a second cell system not reported"]},{"year":2020,"claim":"SETD7 dimethylates PLK1 at K191 to attenuate its kinase activity during early mitosis, and TRIM21 ubiquitinates SETD7 for proteasomal degradation, defining both a mitotic role and a negative upstream regulator of SETD7 protein levels.","evidence":"In vitro methylation, K191R mutagenesis, kinase assays, mitotic arrest analysis; Co-IP, ubiquitination assay for TRIM21-SETD7 axis","pmids":["31863092","32102992"],"confidence":"Medium","gaps":["Whether PLK1 dimethylation occurs on nucleosomes or free PLK1 in mitosis is unknown","TRIM21 regulation of SETD7 not yet validated in non-cancer cell types"]},{"year":2023,"claim":"In cardiomyocytes, energy deprivation activates SETD7, which methylates YAP to enforce cytoplasmic retention and suppress antioxidant gene transcription (MnSOD, CAT), driving mitochondrial ROS and ischemia-reperfusion injury; genetic deletion or pharmacological inhibition rescues this phenotype.","evidence":"SETD7 KO mouse I/R model, (R)-PFI-2 treatment, YAP fractionation, ROS measurement, human ischemic cardiomyopathy tissue","pmids":["35709329"],"confidence":"High","gaps":["Upstream signal activating SETD7 upon energy deprivation not identified","Whether other SETD7 substrates contribute to the cardioprotective phenotype is untested"]},{"year":null,"claim":"Major unresolved questions include: the identity of 'reader' domains or proteins that recognize SETD7-installed methyl marks on most non-histone substrates; the full spectrum of demethylases that reverse SETD7 activity at each substrate; whether SETD7's histone versus non-histone methylation activities are functionally separable in vivo; and the discrepancy between knockout models regarding p53 dependence.","evidence":"","pmids":[],"confidence":"Low","gaps":["No systematic identification of methyl-readers for SETD7-modified non-histone substrates","Demethylase pairing established only for DNMT1 and Rpl29 (LSD1), not for most substrates","Discrepant p53 phenotypes between two independent knockouts remain unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,3,5,7,9,11,12,13,14,19,20,21,23,24,28,31,33,34,35,37,39,41,43]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,11,17,21,40]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[23,43]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[23,28,32,33,43]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,7,8,14,17,20,35]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[9,21,39]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,2,8,22]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[11,41]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,12]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[43]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[17,38]}],"complexes":["YAP-AXIN1-β-catenin-SETD7 complex"],"partners":["YAP1","CTNNB1","RELA","DNMT1","TP53","SMAD7","PLK1","UHRF1"],"other_free_text":[]},"mechanistic_narrative":"SETD7 (SET7/9, KMT7) is a lysine monomethyltransferase that uses its conserved SET domain to transfer a methyl group from S-adenosylmethionine (AdoMet) to histone H3K4 and a broad spectrum of non-histone substrates, thereby regulating chromatin state, transcription factor activity, protein stability, and subcellular localization across diverse signaling pathways. Structural studies reveal a narrow substrate-binding channel connecting opposite enzyme surfaces that accepts only unmethylated or monomethylated lysines, enforcing mono- (or limited di-) methyltransferase product specificity via an SN2 catalytic mechanism, with a conserved K/R-S/T/A recognition motif preceding the target lysine [PMID:12540855, PMID:16415881, PMID:16433545]. SETD7 methylates key signaling effectors including p53 (K372, promoting Tip60-mediated acetylation), NF-κB RelA (K314/K315, triggering proteasomal degradation), DNMT1 (K142, destabilizing the methyltransferase), β-catenin (K180, promoting GSK-3β-mediated degradation), YAP (K494, enforcing cytoplasmic retention to restrain Hippo pathway output), Smad7 (triggering Arkadia-dependent ubiquitination), and PLK1 (K191, attenuating kinase activity during mitosis), placing it at the intersection of the DNA damage response, Wnt, Hippo, TGF-β, and cell cycle pathways [PMID:18280244, PMID:19262565, PMID:19282482, PMID:26116705, PMID:23850191, PMID:27292644, PMID:31863092]. In vivo, Setd7-null mice display expanded intestinal progenitor compartments, glucose intolerance from impaired β-cell insulin secretion, protection from pulmonary fibrosis, and attenuated myocardial ischemia-reperfusion injury, underscoring SETD7's non-redundant physiological roles in tissue homeostasis and stress responses [PMID:23850191, PMID:25713082, PMID:27292644, PMID:35709329]."},"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":"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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mutagenesis identified two C-terminal residues essential for catalytic activity toward H3K4; AdoMet cofactor binding mode and role of invariant residues in catalysis, substrate binding, and AdoMet binding were established.\",\n      \"method\": \"Crystal structure + site-directed mutagenesis + biochemical assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis and biochemical validation in a single study\",\n      \"pmids\": [\"12372304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"High-resolution crystal structure of ternary complex of human SET7/9 with histone H3K4 peptide and AdoMet cofactor shows the peptide and cofactor bind on opposite enzyme surfaces; the target lysine side chain inserts into a narrow channel connecting the two surfaces to access the active site; SET7/9 is exclusively a mono-methylase due to structural constraints.\",\n      \"method\": \"Crystal structure of ternary complex + solution studies\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution ternary complex structure with biochemical validation, replicated across labs\",\n      \"pmids\": [\"12540855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structures of SET7/9 in complex with AdoMet reveal the active site architecture: a binding pocket between the SET domain and c-SET helix for AdoMet in an unusual conformation, a narrow substrate-specific channel permitting only unmethylated lysines, and a catalytic tyrosine residue; SET7/9 can transfer two but not three methyl groups to unmodified H3K4 without substrate dissociation.\",\n      \"method\": \"Crystal structure (1.7 Å and 2.3 Å) + biochemical assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution structures with biochemical validation\",\n      \"pmids\": [\"12514135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SET7/9 (SET9) monomethylates the TBP-associated factor TAF10 at a single lysine in the loop 2 region of its histone-fold domain; methylated TAF10 has increased affinity for RNA polymerase II, linking this modification to preinitiation complex formation; SET9-mediated TAF10 methylation potentiates transcription of a subset of TAF10-dependent genes.\",\n      \"method\": \"In vitro methylation assay, reporter assays, TAF10-null cell complementation with methylation-deficient mutant, Co-IP\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro methylation plus genetic rescue with methylation-deficient mutant and functional readouts\",\n      \"pmids\": [\"15099517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of Pr-Set7 (Set8) ternary complex shows it is exclusively a mono-methylase for H4K20; a histidine residue within the substrate near the target lysine is required for active site completion; the highly variable component of the SET domain governs interactions with the target histone peptide and ensures nucleosome specificity.\",\n      \"method\": \"Crystal structure + NMR + biochemical assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus NMR and biochemical validation\",\n      \"pmids\": [\"15933069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SET7/9 recognizes a conserved K/R-S/T/A motif preceding the target lysine and has a propensity to bind aspartates/asparagines C-terminal to the target; this consensus motif was used to identify novel substrates including TAF7 (methylated at K5 in vitro).\",\n      \"method\": \"Crystal structure with TAF10 peptide + mutagenesis + in vitro methylation assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural analysis with mutagenesis and in vitro biochemistry\",\n      \"pmids\": [\"16415881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Ab initio QM/MM-FE calculations demonstrate that SET7/9-catalyzed methyl transfer is a typical in-line SN2 nucleophilic substitution reaction with ~70% dissociative character; product specificity as a monomethyltransferase is achieved by disrupting near-attack conformations for the dimethylation reaction.\",\n      \"method\": \"Ab initio QM/MM free energy calculations + molecular dynamics simulations\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 computational — consistent with experimental rate constant but no direct mutagenesis\",\n      \"pmids\": [\"16433545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SET7 directly methylates estrogen receptor alpha (ERα) at lysine 302 (K302); this monomethylation stabilizes ERα and is required for efficient ER recruitment to target gene promoters and transactivation; a breast cancer-associated mutation K303R alters K302 methylation in vitro and in vivo. Crystal structure of the SET7-ER peptide complex reveals the molecular basis for substrate recognition.\",\n      \"method\": \"In vitro methylation, crystal structure, ChIP, transactivation assays, cancer mutation analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro methylation, structural data, and multiple cellular functional assays in a single study\",\n      \"pmids\": [\"18471979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SET7/9 functions as a coactivator of NF-κB: it is recruited to NF-κB-regulated inflammatory gene promoters in response to TNF-α, and its gene silencing reduces H3K4 monomethylation at these promoters and decreases NF-κB p65 recruitment, suppressing inflammatory gene induction.\",\n      \"method\": \"siRNA knockdown, ChIP, gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP and knockdown with defined chromatin and transcriptional phenotypes, single lab\",\n      \"pmids\": [\"18650421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Set7/9-mediated monomethylation of p53 at K369 (mouse; K372 in human) is required for subsequent Tip60 acetyltransferase binding to p53 and p53 acetylation; Set7/9 null mouse cells fail to methylate p53, cannot induce p53 downstream targets upon DNA damage, and are predisposed to oncogenic transformation.\",\n      \"method\": \"Set7/9 knockout mouse model, in vivo methylation assay, Co-IP, gene expression analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic null mouse with multiple orthogonal readouts linking methylation to acetylation and downstream function\",\n      \"pmids\": [\"18280244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Set7/9 is required in pancreatic islet beta-cells for normal expression of glucose-stimulated insulin secretion genes (Ins1/2, Glut2, MafA); its depletion causes loss of H3K4 dimethylation and RNA polymerase II recruitment at insulin gene promoters, and impairs glucose-stimulated insulin secretion.\",\n      \"method\": \"siRNA knockdown in insulinoma cells and primary mouse islets, ChIP, Ca2+ mobilization assay, insulin secretion assay\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and functional physiological assays but single lab\",\n      \"pmids\": [\"18984737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SET7 colocalizes and directly interacts with DNMT1 and specifically monomethylates DNMT1 at Lys-142; methylated DNMT1 peaks during S and G2 phases and is prone to proteasome-mediated degradation; SET7 overexpression decreases DNMT1 levels and siRNA knockdown stabilizes DNMT1.\",\n      \"method\": \"Co-localization, direct interaction (pulldown), in vitro methylation, cell cycle analysis, proteasome inhibition, siRNA/OE\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including direct methylation, co-localization, and gain/loss-of-function with defined stability phenotype\",\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 in vitro and in vivo; it monomethylates RelA at K314 and K315; this methylation induces proteasome-mediated degradation of promoter-associated RelA, thereby inhibiting NF-κB action; depletion of Set9 or mutation of methylation sites prolongs NF-κB DNA binding and enhances TNF-α-induced target gene expression.\",\n      \"method\": \"Co-IP, GST pulldown, mass spectrometry, in vitro methylation, proteasome inhibition, siRNA knockdown, mutagenesis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct identification of methylation sites by MS, mutagenesis, and multiple functional assays\",\n      \"pmids\": [\"19262565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Set7/9 (KMT7) monomethylates the HIV Tat protein at lysine 51 located in the RNA-binding domain; Set7/9 itself binds TAR RNA and associates with Tat/P-TEFb complexes at the HIV promoter; knockdown of Set7/9 suppresses Tat transactivation while methylation-deficient Tat (K51A) is unaffected, demonstrating methylation-dependent coactivation of HIV transcription.\",\n      \"method\": \"In vitro methylation, RNA binding assay, ChIP, siRNA knockdown, transactivation assays\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro methylation confirmed at specific site, RNA binding, ChIP, and genetic control (K51A mutant)\",\n      \"pmids\": [\"20227666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The androgen receptor (AR) directly interacts with and is methylated at lysine 632 by SET9 (SETD7); this methylation enhances AR transcriptional activity by facilitating N-C terminal interdomain communication and recruitment to androgen-target gene promoters.\",\n      \"method\": \"Co-IP, in vitro methylation, mutagenesis (K632A), ChIP, transactivation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct methylation demonstrated, site confirmed by mutagenesis, multiple functional readouts\",\n      \"pmids\": [\"20959290\"],\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, enhanced Set7/9-SIRT1 interaction suppresses SIRT1-p53 interaction, abrogating SIRT1-mediated p53 deacetylation and increasing p53 transcriptional activity; this is partially independent of SIRT1 methylation by Set7/9.\",\n      \"method\": \"Co-IP, in vitro binding, in vitro methylation, reporter assays, DNA damage response analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal Co-IP and functional assays, but mechanism partially indirect\",\n      \"pmids\": [\"21245319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In Set7/9-deficient mice (independent knockout strain), p53-dependent transcription and tumor suppression are normal after genotoxic and oncogenic stress, indicating that Set7/9-mediated p53 methylation at K372 is not a major regulatory event for p53 activity in vivo.\",\n      \"method\": \"Independent Set7/9 knockout mouse model, gene expression analysis, oncogenic stress assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — independent genetic null mouse contradicts prior report; single lab but rigorous in vivo epistasis\",\n      \"pmids\": [\"21855805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Set7 directly interacts with MyoD and promotes myoblast differentiation; Set7 knockdown or dominant-negative expression impairs skeletal muscle differentiation and myofibril assembly, reduces H3K4me1, and decreases expression of myocyte enhancer factor 2 and contractile protein genes; Set7 also precludes Suv39h1-mediated H3K9 methylation on myogenic gene promoters.\",\n      \"method\": \"siRNA/dominant-negative expression, Co-IP, ChIP, differentiation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and ChIP with multiple functional differentiation readouts, single lab\",\n      \"pmids\": [\"21859860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Set9 methyltransferase directly methylates FoxO3 at lysine 271 in vitro and in cells; methylation by Set9 decreases FoxO3 protein stability while moderately increasing its transcriptional activity.\",\n      \"method\": \"In vitro methylation, tandem mass spectrometry, methyl-specific antibodies, stability assays, transcriptional reporter assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro methylation with MS site identification and cellular functional assays, single lab\",\n      \"pmids\": [\"22820736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Peptide array methylation analysis determined an optimized target sequence for SET7/9, identifying 91 new peptide substrates from human proteins; nine non-histone proteins (AKA6, CENPC1, MeCP2, MINT, PPARBP, ZDH8, Cullin1, IRF1, TTK) and H2A/H2B were confirmed as SET7/9 substrates in vitro and in vivo; phosphorylation of substrate proteins inhibits SET7/9; SET7/9 can dimethylate MINT lysine in vitro and in vivo.\",\n      \"method\": \"Peptide array methylation, in vitro and in vivo methylation confirmation, mass spectrometry\",\n      \"journal\": \"Chemistry & biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic substrate identification with in vitro and in vivo confirmation\",\n      \"pmids\": [\"21276944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Set7/9 directly methylates the FXR nuclear receptor at lysine 206 in vitro and in vivo; this methylation enhances FXR/RXRα binding to the FXR response element and is required for transcriptional activation of FXR target genes (SHP, BSEP); Set7/9 occupies the FXRE chromatin in vivo.\",\n      \"method\": \"In vitro methylation, mutagenesis (K206R), Co-IP, GST pulldown, mammalian two-hybrid, EMSA, ChIP, reporter assays\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — methylation site confirmed by mutagenesis with multiple complementary methods and functional readouts\",\n      \"pmids\": [\"22345554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SET7/9 methylates the RelA/NF-κB-associated histone methyltransferase SUV39H1 at K105 and K123 in response to DNA damage; this methylation markedly reduces SUV39H1 methyltransferase activity, leading to decreased H3K9me3 in heterochromatin, satellite repeat derepression (heterochromatin relaxation), and genome instability.\",\n      \"method\": \"Co-IP, GST pulldown, Western blot with methyl-specific antibodies, mass spectrometry, MNase 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 — methylation sites identified by MS, enzyme activity assayed, and downstream chromatin consequences measured\",\n      \"pmids\": [\"23509280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SET7/9 methylates histone H1.4 at multiple lysines (K121, K129, K159, K171, K177, K192) in the C-terminal KAK motifs; ADP-ribosylation of H3 by ARTD1 prevents H3 methylation by SET7/9 but allows subsequent H1 methylation; H1 and H3 compete with each other for SET7/9-dependent methylation.\",\n      \"method\": \"In vitro methylation with isolated histones, PAR-ylation assays, site mapping\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro biochemical demonstration with site identification, single lab\",\n      \"pmids\": [\"23289424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SETD7 monomethylates YAP at K494; this methylation is critical for cytoplasmic retention of YAP; Set7-null mice have a larger intestinal progenitor compartment coinciding with increased YAP target gene expression, demonstrating in vivo regulation of the Hippo pathway by Set7-dependent YAP methylation.\",\n      \"method\": \"Set7 knockout mice, in vitro methylation, subcellular fractionation, intestinal progenitor analysis, gene expression\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with specific methylation site identified and mechanistic link to YAP localization established\",\n      \"pmids\": [\"23850191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SET7/9 methylates ARTD1 (PARP1) at K508 in vitro and in vivo; ARTD1 methylation by SET7/9 enhances poly-ADP-ribose synthesis upon oxidative stress and promotes ARTD1 recruitment to DNA damage sites in a SET7/9-dependent manner; ARTD1 auto-modification inhibits its methylation by SET7/9.\",\n      \"method\": \"In vitro methylation, in vivo methylation (methyl-specific antibody), laser irradiation, PAR formation assay\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo methylation confirmed, functional PAR assay performed, single lab\",\n      \"pmids\": [\"24088713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SET7/9 negatively regulates the antiviral restriction factor IFITM3 by monomethylating it at K88; viral infection (VSV, influenza A) promotes IFITM3-SET7 interaction to increase IFITM3-K88me1 and reduce antiviral activity; IFN-α reduces IFITM3-K88me1 levels.\",\n      \"method\": \"In vitro and in vivo methylation, viral infection assays, Co-IP, methyl-specific antibody\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct methylation shown with functional viral restriction readout, single lab\",\n      \"pmids\": [\"24129573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"(R)-PFI-2 is a potent (Ki ~0.33 nM), selective, cell-active inhibitor of SETD7 that occupies the substrate peptide binding groove in a cofactor-dependent, substrate-competitive manner, making direct contact with the AdoMet methyl group; in cells, it phenocopies Setd7 deficiency by modulating YAP localization and Hippo pathway signaling.\",\n      \"method\": \"Biochemical inhibition assay, X-ray crystallography, chemoproteomics, cell-based YAP localization assay, MEF Setd7-null comparison\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure of inhibitor-enzyme complex, biochemical Ki measurement, and cellular target engagement validated\",\n      \"pmids\": [\"25136132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Set7 methylates HIF-1α at K32 and HIF-2α at K29; this methylation inhibits HIF-α transcriptional activity by impairing HIF-α occupancy at hypoxia response elements; Set7-null fibroblasts show upregulated HIF target genes and increased glucose uptake/ATP levels under hypoxia.\",\n      \"method\": \"In vitro methylation, Set7-null fibroblasts, shRNA knockdown, ChIP, metabolic assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro methylation with in vivo genetic null and functional metabolic phenotype, single lab\",\n      \"pmids\": [\"25897119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SET7/9 interacts with and methylates β-catenin at K180 in vitro and in vivo; methylated β-catenin is recognized by GSK-3β for degradation; non-methylatable β-catenin (K180R) has a longer half-life; SET7/9 knockdown or K180R mutation enhances Wnt/β-catenin target gene expression and cancer cell growth.\",\n      \"method\": \"Co-IP, in vitro methylation, mass spectrometry, mutagenesis, stability assays, gene expression\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — methylation site confirmed by MS and mutagenesis, downstream degradation mechanism defined, multiple functional assays\",\n      \"pmids\": [\"26116705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Set7/9 methylates the androgen receptor at K630; alanine substitution prevents methylation in vitro and in vivo; Set7 overexpression potentiates AR-mediated transactivation while depletion inhibits AR activity; methylation promotes AR N-C terminal interaction and co-occupies androgen response elements with activated histone marks.\",\n      \"method\": \"In vitro methylation, mutagenesis (K630A), Co-IP, ChIP, transactivation assays\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct methylation, mutagenesis, and multiple functional readouts, single lab; corroborates earlier finding at adjacent K632\",\n      \"pmids\": [\"21273441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KMT Set7/9 physically interacts with Mdm2 and regulates its expression; several cancer cell lines with inverse expression of Set7/9 and Mdm2 show altered sensitivity to genotoxic stress, placing Set7/9 upstream of Mdm2 in the DNA damage response.\",\n      \"method\": \"Co-IP, gene expression, siRNA, cell viability assays, bioinformatics\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP and expression analysis without direct mechanistic reconstitution\",\n      \"pmids\": [\"26317544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Set7/9 methylates Pdx1 at K123 and K131; K131 methylation (but not K123) is required for Set7/9-mediated augmentation of Pdx1 transcriptional activity; conditional beta-cell-specific Set7 knockout mice exhibit glucose intolerance and impaired glucose-stimulated insulin secretion with reduced Pdx1 target gene expression.\",\n      \"method\": \"Mass spectrometry, mutagenesis, Co-IP, reporter assays, conditional knockout mouse, glucose tolerance test\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — MS identification of methylation sites, mutagenesis, conditional KO with physiological phenotype\",\n      \"pmids\": [\"25713082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SETD7 is part of a complex containing YAP, AXIN1, and β-catenin; SETD7-dependent methylation of YAP facilitates Wnt-induced nuclear accumulation of β-catenin; SETD7 is required for Wnt-driven intestinal tumorigenesis and regeneration, mechanistically linking the Hippo/YAP and Wnt/β-catenin pathways.\",\n      \"method\": \"Co-IP, SETD7 KO mouse intestinal tumorigenesis model, β-catenin nuclear fractionation, gene expression\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model plus complex identification and defined molecular mechanism linking two pathways\",\n      \"pmids\": [\"27046831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Set9 methyltransferase promotes TGF-β signaling by methylating the inhibitory Smad7, which promotes Smad7 interaction with the E3 ligase Arkadia and subsequent ubiquitination-dependent degradation of Smad7; Set9-deficient mice show elevated Smad7 levels and are protected from bleomycin- and Ad-TGF-β-induced pulmonary fibrosis.\",\n      \"method\": \"In vitro methylation, Co-IP, ubiquitination assay, Set9-KO mouse fibrosis models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct methylation, interaction with E3 ligase, and in vivo genetic validation in two fibrosis models\",\n      \"pmids\": [\"27292644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Set7 methylates Gli3 (full-length form) at K436 and K595; methylation at K436 increases Gli3 stability and at K595 increases its DNA-binding ability, resulting in enhanced Shh signaling activation; Gli3 methylation contributes to tumor growth and metastasis in non-small cell lung cancer.\",\n      \"method\": \"In vitro methylation, mutagenesis, stability assays, DNA-binding assays, in vitro/in vivo tumor models\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro methylation with mutagenesis, functional phenotypes in vitro and in vivo, single lab\",\n      \"pmids\": [\"27146893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SET7/9 methylates YY1 transcription factor at K173 and K411; this methylation regulates YY1 DNA-binding activity both in vitro and at specific genomic loci in cells and is involved in YY1-regulated gene transcription and cell proliferation.\",\n      \"method\": \"In vitro methylation, mutagenesis, EMSA, ChIP, reporter assays, cell proliferation assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct methylation with mutagenesis and functional readouts, single lab\",\n      \"pmids\": [\"26902152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"An asparagine residue in SET7/9 that mediates AdoMet sulfur-oxygen chalcogen bonding enhances AdoMet binding affinity over the product AdoHcy; structural, biochemical, and computational analyses show that S···O chalcogen bonds contribute to AdoMet recognition and enable substrate-product discrimination.\",\n      \"method\": \"X-ray crystallography, mutagenesis, biochemical binding assays, quantum mechanical calculations\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis and computational corroboration\",\n      \"pmids\": [\"26713889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rpl29 (ribosomal protein L29) is a major substrate of Set7/9; Rpl29 K5 is methylated exclusively by Set7/9 and can be demethylated by Lsd1; Rpl29 K5 methylation affects Rpl29 subcellular localization but not global protein synthesis; Rpl29 K5 methylation serves as a reliable cellular biomarker for Set7/9 activity validated by (R)-PFI-2 treatment.\",\n      \"method\": \"In vitro methylation, methyl-specific antibody, siRNA, subcellular fractionation, inhibitor treatment (R)-PFI-2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — exclusive substrate identification with writer/eraser confirmed, functional localization phenotype, inhibitor validation\",\n      \"pmids\": [\"29959229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Setd7 facilitates the transition from activated, proliferating myogenic stem cells (MuSCs) to differentiation-primed progenitors by regulating nuclear accumulation of β-catenin; genetic or pharmacological inhibition of Setd7 promotes in vitro MuSC expansion and enhances engraftment and therapeutic potential upon transplantation.\",\n      \"method\": \"Genetic Setd7 deletion, pharmacological inhibition (R)-PFI-2, β-catenin nuclear fractionation, transplantation assays, muscular dystrophy preclinical model\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological KO with mechanistic β-catenin readout and in vivo therapeutic validation\",\n      \"pmids\": [\"29395054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UHRF1 is methylated by SET7 and demethylated by LSD1; DNA damage induces UHRF1 methylation, and UHRF1 phosphorylation in S phase is a prerequisite for its interaction with SET7; UHRF1 methylation promotes polyubiquitin chain conjugation to PCNA and facilitates homologous recombination for DNA double-strand break repair; SET7-mediated UHRF1 methylation is essential for cell viability against DNA damage.\",\n      \"method\": \"In vitro methylation, Co-IP, ubiquitination assay, siRNA, homologous recombination reporter assay, cell viability assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct methylation and functional DNA repair readouts, single lab\",\n      \"pmids\": [\"30357346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The SUMO-specific isopeptidase SENP3 associates with SETD7 and deSUMOylates it; by recruiting deSUMOylated SETD7 to the MyHC-II gene locus, SENP3 promotes SETD7 association with active RNA Pol II and precludes Suv39h1; SENP3 is degraded in cachexia, impairing SETD7-dependent MyHC-II expression and sarcomere organization.\",\n      \"method\": \"Co-IP, deSUMOylation assay, ChIP, siRNA knockdown, sarcomere morphology analysis, muscle contractility assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular mechanism defined by multiple biochemical and cell biological approaches, single lab\",\n      \"pmids\": [\"31141694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SET7/9 dimethylates PLK1 at K191 during early mitosis, reducing PLK1 kinase activity by limiting ATP utilization; overexpression of non-methylatable PLK1 (K191R) or chemical inhibition of SET7/9 causes mitotic arrest due to destabilized kinetochore-microtubule attachments, revealing methylation-dependent regulation of accurate chromosome segregation.\",\n      \"method\": \"In vitro methylation, mutagenesis (K191R), kinase assays, mitotic arrest analysis, SET7/9 inhibitor treatment\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct methylation with mutagenesis and kinase activity assay, functional mitotic phenotype, single lab\",\n      \"pmids\": [\"31863092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM21 physically associates with SET7/9 and functions as a major negative regulator upstream of SET7/9 through a proteasome-dependent ubiquitination mechanism; SET7/9 promotes breast cancer cell proliferation, migration, and invasion via activation of RUNX2.\",\n      \"method\": \"Co-IP, GST pulldown, ubiquitination assay, ChIP-seq, cell proliferation/migration/invasion assays, xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct TRIM21-SET7/9 interaction with ubiquitination mechanism and functional cancer phenotypes\",\n      \"pmids\": [\"32102992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SETD7 is activated upon energy deprivation in cardiomyocytes and methylates YAP, leading to YAP cytosolic retention and impaired transcription of antioxidant genes MnSOD and CAT; this drives mitochondrial ROS accumulation, organelle swelling, and apoptosis; pharmacological SETD7 inhibition with (R)-PFI-2 or genetic SETD7 deletion restores YAP nuclear localization and MnSOD/CAT expression, attenuating myocardial ischemia/reperfusion injury.\",\n      \"method\": \"SETD7 KO mouse I/R model, (R)-PFI-2 treatment, YAP nuclear fractionation, ROS measurement, mitochondrial morphology, Ca2+-activated tension, NRVMs, human ICM LV samples\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and pharmacological inhibition with mechanistic YAP methylation-localization link and multiple orthogonal readouts, confirmed in human tissue\",\n      \"pmids\": [\"35709329\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SETD7 (SET7/9) is a lysine monomethyltransferase that uses a narrow substrate-binding channel and an SN2 catalytic mechanism to transfer a single methyl group from AdoMet to histone H3K4 and a broad spectrum of non-histone substrates—including p53, ERα, DNMT1, NF-κB RelA, YAP, β-catenin, UHRF1, PLK1, Smad7, TAF10, AR, FXR, HIF-1α/2α, and others—thereby regulating substrate stability, subcellular localization, protein-protein interactions, and transcriptional activity in pathways controlling inflammation, DNA damage response, Hippo/Wnt signaling, cell cycle progression, and differentiation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SETD7 (SET7/9, KMT7) is a lysine monomethyltransferase that uses its conserved SET domain to transfer a methyl group from S-adenosylmethionine (AdoMet) to histone H3K4 and a broad spectrum of non-histone substrates, thereby regulating chromatin state, transcription factor activity, protein stability, and subcellular localization across diverse signaling pathways. Structural studies reveal a narrow substrate-binding channel connecting opposite enzyme surfaces that accepts only unmethylated or monomethylated lysines, enforcing mono- (or limited di-) methyltransferase product specificity via an SN2 catalytic mechanism, with a conserved K/R-S/T/A recognition motif preceding the target lysine [PMID:12540855, PMID:16415881, PMID:16433545]. SETD7 methylates key signaling effectors including p53 (K372, promoting Tip60-mediated acetylation), NF-κB RelA (K314/K315, triggering proteasomal degradation), DNMT1 (K142, destabilizing the methyltransferase), β-catenin (K180, promoting GSK-3β-mediated degradation), YAP (K494, enforcing cytoplasmic retention to restrain Hippo pathway output), Smad7 (triggering Arkadia-dependent ubiquitination), and PLK1 (K191, attenuating kinase activity during mitosis), placing it at the intersection of the DNA damage response, Wnt, Hippo, TGF-β, and cell cycle pathways [PMID:18280244, PMID:19262565, PMID:19282482, PMID:26116705, PMID:23850191, PMID:27292644, PMID:31863092]. In vivo, Setd7-null mice display expanded intestinal progenitor compartments, glucose intolerance from impaired β-cell insulin secretion, protection from pulmonary fibrosis, and attenuated myocardial ischemia-reperfusion injury, underscoring SETD7's non-redundant physiological roles in tissue homeostasis and stress responses [PMID:23850191, PMID:25713082, PMID:27292644, PMID:35709329].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Determining the three-dimensional architecture of SET7/9 established how the N-terminal β-sheet and conserved SET domain organize the catalytic center around AdoMet, and identified two C-terminal residues essential for H3K4 methylation.\",\n      \"evidence\": \"Crystal structure with site-directed mutagenesis and biochemical assays on recombinant human SET7/9\",\n      \"pmids\": [\"12372304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No substrate peptide in the structure; substrate-binding mode unknown\", \"Product specificity (mono- vs. di- vs. tri-methyl) not yet explained\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Ternary complex structures resolved how the target lysine threads through a narrow channel between cofactor and substrate binding surfaces, explaining SET7/9's exclusive monomethyltransferase activity and the structural basis for substrate specificity.\",\n      \"evidence\": \"High-resolution crystal structures of SET7/9–H3K4 peptide–AdoMet ternary complex plus solution studies\",\n      \"pmids\": [\"12540855\", \"12514135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether channel geometry permits any dimethylation in special contexts was debated\", \"Non-histone substrate recognition not yet addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The discovery that SET7/9 monomethylates the non-histone protein TAF10, enhancing its affinity for RNA Pol II and potentiating transcription, established the precedent that SET7/9 functions beyond histone modification.\",\n      \"evidence\": \"In vitro methylation of TAF10, reporter assays, and genetic rescue with methylation-deficient TAF10 mutant in TAF10-null cells\",\n      \"pmids\": [\"15099517\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological importance in vivo not tested\", \"Whether other TAF subunits are substrates was unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Definition of a conserved K/R-S/T/A substrate recognition motif, together with QM/MM-computed SN2 catalytic mechanism, provided predictive rules for new substrate identification and explained product specificity at the quantum-mechanical level.\",\n      \"evidence\": \"Crystal structure with TAF10 peptide, mutagenesis, peptide methylation assays, and ab initio QM/MM free energy calculations\",\n      \"pmids\": [\"16415881\", \"16433545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Motif-based prediction not yet validated proteome-wide\", \"Computational mechanism awaited experimental kinetic isotope effect confirmation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Multiple studies revealed that SET7/9 methylates diverse transcription factors and signaling proteins—ERα (K302, stabilization), p53 (K372, enabling Tip60 acetylation and DNA damage response), and NF-κB-target promoters (H3K4me1 deposition)—establishing it as a broad-spectrum signaling methyltransferase.\",\n      \"evidence\": \"Crystal structure of SET7–ERα peptide complex, Set7/9 knockout mouse p53 methylation studies, and ChIP/siRNA in TNF-α-stimulated cells\",\n      \"pmids\": [\"18471979\", \"18280244\", \"18650421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative importance of histone vs. non-histone methylation at each locus unclear\", \"An independent KO later questioned in vivo p53 dependence on Set7/9\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of DNMT1-K142 and RelA-K314/K315 as SET7/9 substrates whose methylation triggers proteasomal degradation established a recurring mechanism: methylation marks proteins for destruction.\",\n      \"evidence\": \"Direct in vitro methylation, mass spectrometry, proteasome inhibitor rescue, siRNA and overexpression in human cells\",\n      \"pmids\": [\"19282482\", \"19262565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The E3 ligase(s) recognizing methyl-DNMT1 were unknown\", \"Whether RelA methylation-degradation operates in all NF-κB-dependent contexts was untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"An independent Set7/9-null mouse showed normal p53-dependent transcription and tumor suppression after genotoxic and oncogenic stress, challenging the earlier model that Set7/9-mediated p53-K372 methylation is essential for the DNA damage response in vivo.\",\n      \"evidence\": \"Independent Set7/9 knockout mouse, gene expression analysis, oncogenic stress assays\",\n      \"pmids\": [\"21855805\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Discrepancy with the earlier KO study not fully resolved—may reflect strain or context differences\", \"Whether Set7/9 has redundant or compensated roles in p53 activation in specific tissues remains open\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Systematic peptide array screening expanded the validated substrate repertoire to dozens of proteins (including MeCP2, Cullin1, IRF1, histones H2A/H2B, H1.4) and demonstrated that substrate phosphorylation inhibits SET7/9, revealing crosstalk between modification pathways.\",\n      \"evidence\": \"Peptide array methylation, in vitro and in vivo confirmation by mass spectrometry\",\n      \"pmids\": [\"21276944\", \"23289424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many array-identified substrates lack in vivo functional validation\", \"Stoichiometry and biological significance of most new substrates unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that SETD7 monomethylates YAP at K494 to enforce its cytoplasmic retention, with Set7-null mice showing expanded intestinal progenitors and elevated YAP target genes, established SETD7 as a Hippo pathway regulator in vivo.\",\n      \"evidence\": \"Set7 knockout mice, in vitro methylation, subcellular fractionation, intestinal progenitor cell analysis\",\n      \"pmids\": [\"23850191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The cytoplasmic reader recognizing methyl-YAP was not identified\", \"Whether YAP methylation is dynamically reversed by a demethylase was unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Methylation of β-catenin at K180 by SET7/9, promoting GSK-3β-dependent degradation, together with methylation of Pdx1 activating insulin gene expression in β-cells, expanded the in vivo roles of SETD7 to Wnt signaling and glucose homeostasis.\",\n      \"evidence\": \"Mass spectrometry site identification, mutagenesis (K180R), conditional β-cell KO mouse with glucose intolerance phenotype\",\n      \"pmids\": [\"26116705\", \"25713082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether β-catenin K180 methylation cooperates with YAP methylation in intestinal tumorigenesis was unknown\", \"The demethylase counteracting β-catenin methylation was not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"SETD7 was shown to integrate Hippo and Wnt pathways: it exists in a complex with YAP, AXIN1, and β-catenin, and is required for Wnt-driven intestinal tumorigenesis and regeneration, while also methylating Smad7 to promote TGF-β signaling via Arkadia-mediated degradation.\",\n      \"evidence\": \"SETD7 KO intestinal tumorigenesis model, Co-IP of quaternary complex, Set9-KO pulmonary fibrosis models\",\n      \"pmids\": [\"27046831\", \"27292644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SETD7 is dynamically recruited to the AXIN1 destruction complex is unclear\", \"Whether the Smad7 methylation-degradation axis operates in all TGF-β contexts is untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of Rpl29-K5 as a major and exclusive SET7/9 substrate reversible by LSD1 provided a reliable cellular biomarker for SETD7 activity, validated with the selective chemical probe (R)-PFI-2.\",\n      \"evidence\": \"In vitro methylation, methyl-specific antibody, (R)-PFI-2 inhibitor treatment, subcellular fractionation\",\n      \"pmids\": [\"29959229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Rpl29 methylation beyond localization change is unknown\", \"Whether Rpl29 methylation affects ribosome biogenesis or translation of specific mRNAs was not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"SET7-mediated methylation of UHRF1, dependent on prior S-phase phosphorylation, promotes PCNA polyubiquitination and homologous recombination repair, placing SETD7 directly in the DNA double-strand break repair pathway.\",\n      \"evidence\": \"In vitro methylation, Co-IP, HR reporter assay, siRNA, cell viability after DNA damage\",\n      \"pmids\": [\"30357346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The specific UHRF1 methylation site was not mapped by mutagenesis\", \"Independent replication in a second cell system not reported\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"SETD7 dimethylates PLK1 at K191 to attenuate its kinase activity during early mitosis, and TRIM21 ubiquitinates SETD7 for proteasomal degradation, defining both a mitotic role and a negative upstream regulator of SETD7 protein levels.\",\n      \"evidence\": \"In vitro methylation, K191R mutagenesis, kinase assays, mitotic arrest analysis; Co-IP, ubiquitination assay for TRIM21-SETD7 axis\",\n      \"pmids\": [\"31863092\", \"32102992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PLK1 dimethylation occurs on nucleosomes or free PLK1 in mitosis is unknown\", \"TRIM21 regulation of SETD7 not yet validated in non-cancer cell types\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In cardiomyocytes, energy deprivation activates SETD7, which methylates YAP to enforce cytoplasmic retention and suppress antioxidant gene transcription (MnSOD, CAT), driving mitochondrial ROS and ischemia-reperfusion injury; genetic deletion or pharmacological inhibition rescues this phenotype.\",\n      \"evidence\": \"SETD7 KO mouse I/R model, (R)-PFI-2 treatment, YAP fractionation, ROS measurement, human ischemic cardiomyopathy tissue\",\n      \"pmids\": [\"35709329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signal activating SETD7 upon energy deprivation not identified\", \"Whether other SETD7 substrates contribute to the cardioprotective phenotype is untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include: the identity of 'reader' domains or proteins that recognize SETD7-installed methyl marks on most non-histone substrates; the full spectrum of demethylases that reverse SETD7 activity at each substrate; whether SETD7's histone versus non-histone methylation activities are functionally separable in vivo; and the discrepancy between knockout models regarding p53 dependence.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No systematic identification of methyl-readers for SETD7-modified non-histone substrates\", \"Demethylase pairing established only for DNMT1 and Rpl29 (LSD1), not for most substrates\", \"Discrepant p53 phenotypes between two independent knockouts remain unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 7, 9, 11, 12, 13, 14, 19, 20, 21, 23, 24, 28, 31, 33, 34, 35, 37, 39, 41, 43]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 11, 17, 21, 40]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [23, 43]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [23, 28, 32, 33, 43]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 7, 8, 14, 17, 20, 35]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [9, 21, 39]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 2, 8, 22]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [11, 41]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [43]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [17, 38]}\n    ],\n    \"complexes\": [\n      \"YAP-AXIN1-β-catenin-SETD7 complex\"\n    ],\n    \"partners\": [\n      \"YAP1\",\n      \"CTNNB1\",\n      \"RELA\",\n      \"DNMT1\",\n      \"TP53\",\n      \"SMAD7\",\n      \"PLK1\",\n      \"UHRF1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}