{"gene":"SETD1A","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2001,"finding":"Set1 (yeast ortholog of SETD1A) is the sole histone H3 lysine 4 methyltransferase in S. cerevisiae; deletion of SET1 abolishes all H3K4 methylation in vivo, and this can be rescued by re-expression of SET1.","method":"Genetic deletion, in vivo histone methylation assay with methyl-specific antiserum, complementation rescue","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vivo enzymatic loss-of-function with rescue, independently replicated across multiple labs","pmids":["11751634","11742990"],"is_preprint":false},{"year":2001,"finding":"Set1 exists as an eight-subunit complex (Set1C/COMPASS), which includes an Ash2/Bre2 homologue; complex integrity requires Set1, and loss of Set1 disrupts the complex.","method":"Co-immunoprecipitation, mass spectrometry, biochemical fractionation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP + MS, replicated across multiple labs and organisms","pmids":["11742990"],"is_preprint":false},{"year":2003,"finding":"Set1 is recruited to the 5' portion of active mRNA coding regions by the Pol II elongation machinery; Set1 physically interacts with the Ser5-phosphorylated (but not Ser2-phosphorylated) form of the Pol II CTD, and its recruitment depends on the TFIIH-associated CTD kinase and on Rtf1/Paf1 components of the Paf1 complex.","method":"Chromatin immunoprecipitation (ChIP), co-immunoprecipitation, genetic epistasis with CTD kinase and Paf1 complex mutants","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP + Co-IP + genetic epistasis, replicated in multiple studies","pmids":["12667453"],"is_preprint":false},{"year":2003,"finding":"Human Set1/Ash2 histone methyltransferase complex (containing SETD1A) methylates histone H3 at Lys4 but not if the neighboring K9 residue is already methylated; HCF-1 tethers this Set1/Ash2 HMT complex together with the Sin3 HDAC complex, and the transcriptional activator VP16 selectively binds HCF-1 associated with Set1/Ash2 in the absence of Sin3.","method":"In vitro histone methyltransferase assay, co-immunoprecipitation, domain mapping","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with substrate specificity analysis plus reciprocal Co-IP, single lab but multiple orthogonal methods","pmids":["12670868"],"is_preprint":false},{"year":2005,"finding":"Human CFP1 (CXXC finger protein 1) is a component of the mammalian SETD1A/Set1 complex; the complex produces mono-, di-, and trimethylated H3K4 in vitro; CFP1 and SETD1A co-localize to nuclear speckles associated with euchromatin; cells lacking CFP1 show elevated H3K4 methylation, indicating CFP1 restricts SETD1A activity.","method":"Co-immunoprecipitation, mass spectrometry, in vitro methyltransferase assay, confocal microscopy, genetic knockout of CFP1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro activity, Co-IP/MS subunit identification, live imaging localization, loss-of-function phenotype, multiple orthogonal methods in one study","pmids":["16253997"],"is_preprint":false},{"year":2005,"finding":"H2B ubiquitylation at K123 is dispensable for monomethylation of H3K4 by Set1 but is required for the transition from monomethylation to di- and trimethylation (processive methylation); Dot1 binding to chromatin is normal without H2Bub, suggesting ubiquitylation regulates processivity rather than recruitment.","method":"Chromatin immunoprecipitation, mass spectrometry, genetic mutation of H2B K123","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP + MS distinguishing mono/di/trimethylation states, genetic epistasis, replicated concept in multiple papers","pmids":["16039595"],"is_preprint":false},{"year":2005,"finding":"The N-terminal region of Set1 is required for global H3K4 trimethylation; Set1 trimethyl-defective N-terminal mutants are defective in telomere, rDNA, HML, and HMR silencing, while mono- and/or dimethylation by Set1 is sufficient for cell growth.","method":"Yeast genetics, site-directed mutagenesis, chromatin immunoprecipitation, silencing assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mutagenesis with silencing and growth phenotype readouts, single lab","pmids":["15964832"],"is_preprint":false},{"year":2005,"finding":"Set1 methyltransferase is required for methylation of conserved lysines in the kinetochore protein Dam1; Dam1 methylation by Set1 inhibits Ipl1 Aurora kinase-mediated phosphorylation of flanking serines, with SET1 deletion suppressing chromosome loss in ipl1-2 cells; this function is independent of Set1's role in H3K4 methylation and transcription.","method":"Genetic epistasis (suppressor analysis of ipl1-2), biochemical methylation assay of Dam1, genetic double-mutant analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis + in vitro methylation of non-histone substrate + functional rescue, published in Cell, single lab but multiple orthogonal approaches","pmids":["16143104"],"is_preprint":false},{"year":2005,"finding":"The RNA recognition motif 1 (RRM1) of Set1, when combined with a newly identified RRM2, specifically binds RNA in vitro; RRM1 mutation destabilizes Set1 and alters the ratio of H3K4 di- to trimethylation at active genes, reducing trimethylation while increasing dimethylation at 5'-coding regions.","method":"Crystal structure of RRM1, RNA-binding assay in vitro, in vivo H3K4 methylation analysis by ChIP, site-directed mutagenesis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus in vitro binding assay plus in vivo functional mutagenesis, single lab with multiple orthogonal methods","pmids":["15775977"],"is_preprint":false},{"year":2006,"finding":"Within the Set1 complex, Swd1 and Swd3 are required for complex integrity and Set1 stability; the Bre2-Sdc1 heterodimer is required for H3K4 trimethylation at the 5' end of active genes; Set1C associates with both Ser5- and Ser2-phosphorylated forms of Pol II, indicating persistent association throughout transcription.","method":"Co-immunoprecipitation, genetic deletion of individual subunits, western blot for Set1 levels, ChIP","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — systematic protein interaction mapping within the complex combined with in vivo chromatin analysis, multiple genetic deletions","pmids":["16921172"],"is_preprint":false},{"year":2007,"finding":"The Wdr82 component of the human SETD1A complex interacts with the RNA recognition motif of SETD1A and binds to the Ser5-phosphorylated CTD of RNA Pol II (but not unphosphorylated or Ser2-phosphorylated CTD); siRNA depletion of Wdr82 decreases SETD1A expression and its occupancy at transcription start sites and reduces H3K4me3 at those sites, without altering Pol II occupancy or target gene expression.","method":"Co-immunoprecipitation, peptide binding assays, chromatin immunoprecipitation, siRNA knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP, functional KD with multiple readouts, mechanistically defines Wdr82 as CTD-binding adaptor for SETD1A","pmids":["17998332"],"is_preprint":false},{"year":2007,"finding":"HCF-1 recruits SETD1A (Set1) and MLL1 histone methyltransferases to herpesvirus immediate early promoters, leading to H3K4me3 and transcriptional activation; HCF-1 is required for this chromatin modification step but not for assembly of the basal RNAPII complex.","method":"ChIP at viral promoters, epistasis with HCF-1, promoter reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with functional epistasis on viral promoters, single lab","pmids":["17578910"],"is_preprint":false},{"year":2008,"finding":"Wdr82 is a specific component of the human Set1A/B complexes but not MLL1-4 complexes; siRNA knockdown of Wdr82 reduces H3K4 trimethylation levels in vivo; in vitro, the Set1 complex is a more robust H3K4 trimethylase than MLL complexes.","method":"Affinity purification/mass spectrometry, RNAi knockdown, in vitro histone methyltransferase assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic reconstitution combined with in vivo RNAi and AP-MS, multiple orthogonal methods","pmids":["18838538"],"is_preprint":false},{"year":2009,"finding":"Tyr1052 (the Phe/Tyr switch) in the catalytic domain of Set1 is essential for H3K4 trimethylation by COMPASS; mutation Y1052F suppresses the trimethylation defect caused by loss of Cps40/Spp1, but does not suppress defects from loss of H2B monoubiquitination, indicating Tyr1052 and Cps40 function together downstream of and independently of H2Bub.","method":"Homology modeling, site-directed mutagenesis, in vivo H3K4 methylation analysis, ChIP","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structure-guided mutagenesis with in vivo functional readouts, single lab","pmids":["19398585"],"is_preprint":false},{"year":2009,"finding":"H3K4 dimethylation by Set1 recruits the Set3 histone deacetylase complex via the Set3 PHD finger to 5' transcribed regions, where Hos2 and Hst1 deacetylate histones; this reduces histone acetylation near 5' ends of genes and positively affects transcription elongation.","method":"Genetic epistasis, ChIP, PHD finger binding assay, growth assays on mycophenolic acid","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis + ChIP + domain binding, published in Cell, mechanistic pathway placed Set1→H3K4me2→Set3C recruitment","pmids":["19379692"],"is_preprint":false},{"year":2009,"finding":"CFP1 restricts the SETD1A complex to euchromatin; in CFP1-null ES cells, SETD1A and H3K4me3 mislocalize to heterochromatin; both the DNA-binding activity of CFP1 and its interaction with the SETD1A complex are required for proper SETD1A genomic targeting.","method":"Confocal microscopy, genetic knockout (CXXC1-/-), structure-function analysis of CFP1 point mutations and truncations","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization by imaging tied to functional consequence, structure-function mutagenesis, single lab","pmids":["19951360"],"is_preprint":false},{"year":2012,"finding":"WDR5 binds the Win (WDR5-interacting) motifs of MLL2-4, SET1A, and SET1B; crystal structures of WDR5-Win complexes show binding is achieved by plasticity of WDR5's peptidyl-arginine-binding cleft; WDR5 is important for optimal stimulation of SET1A methyltransferase activity by the RbBP5-ASH2L heterodimer.","method":"Crystal structure determination, biochemical binding assays, in vitro methyltransferase assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures plus enzymatic activity assays, mechanistically defines WDR5 role in SET1A complex assembly","pmids":["22266653"],"is_preprint":false},{"year":2013,"finding":"TET2 and TET3 directly interact with OGT; TET2/3-OGT co-localize on chromatin at H3K4me3-enriched active promoters; reduction of TET2/3 or OGT activity decreases H3K4me3 and transcription; HCF1, a SET1/COMPASS component, is a specific GlcNAcylation target of TET2/3-OGT, and HCF1 modification is important for COMPASS integrity; TET proteins and OGT promote chromatin binding of SETD1A.","method":"Co-immunoprecipitation, ChIP, OGT activity assays, knockdown of TET2/3 and OGT, mass spectrometry identification of HCF1 GlcNAcylation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, enzymatic assay, MS-PTM identification), single lab but comprehensive","pmids":["23353889"],"is_preprint":false},{"year":2013,"finding":"The n-SET domain of Set1 (but not Swd2) is essential for H2Bub-dependent H3K4 methylation on reconstituted chromatin templates; Spp1 (CFP1 homolog) is conditionally involved in this crosstalk; this mechanism is conserved in the human Set1 complex.","method":"In vitro histone methyltransferase assay with reconstituted yeast Set1 complex and fully ubiquitylated H2B chromatin template, n-SET domain mutagenesis, genetic analyses","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution on chromatin template with mutagenesis, extended to human complex, single lab","pmids":["23453808"],"is_preprint":false},{"year":2013,"finding":"In vitro studies with recombinant chromatin and purified human SET1 complex (SET1C) show robust H3K4me3 that is dependent on p53/p300-mediated H3 acetylation; SET1C directly interacts with p53 and p300; DNA-damage induces p53-SET1C interaction in cells with enrichment of SET1C and H3K4me3 at the p21/WAF1 promoter; H3K4me3 and transcription codepend on both SET1C and p300.","method":"In vitro transcription/methylation assay with recombinant chromatin, Co-IP, ChIP, cell-based assays with DNA damage","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution on recombinant chromatin plus Co-IP plus ChIP in cells, multiple orthogonal methods, published in Cell","pmids":["23870121"],"is_preprint":false},{"year":2013,"finding":"Quantitative mass spectrometry revealed Bod1 protein as a discriminator between SET1B and SET1A complexes, distinguishing their subunit composition; DPY30 is a genuine subunit of both SET1/MLL complexes and the NURF chromatin remodeling complex.","method":"Label-free quantitative mass spectrometry, affinity purification","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative AP-MS with stoichiometry determination, single lab","pmids":["23508102"],"is_preprint":false},{"year":2014,"finding":"Mouse Setd1a is required for gastrulation; Setd1a knockout embryos implant but fail to progress past the epiblast stage; deletion of Setd1a in ES cells causes rapid loss of bulk H3K4 methylation, pluripotency gene expression, and proliferation with G1 arrest; Setd1b overexpression cannot rescue the proliferation defects caused by Setd1a loss.","method":"Conditional gene knockout in mice, ES cell deletion, western blot for H3K4 methylation, flow cytometry for cell cycle","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular and developmental phenotypes, multiple readouts, single lab","pmids":["24550110"],"is_preprint":false},{"year":2015,"finding":"SETD1A suppresses BTG2 expression through induction of BTG2-targeting miRNAs, not through direct chromatin repression of BTG2; this indirect miRNA-dependent mechanism regulates cell cycle progression in vitro and tumorigenesis in mouse xenograft models.","method":"shRNA screen of 43 histone KMTs, miRNA profiling, cell cycle assays, xenograft tumor models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional screen with mechanistic follow-up (miRNA pathway placement), xenograft validation, single lab","pmids":["26394836"],"is_preprint":false},{"year":2015,"finding":"Biochemical reconstitution of each human SET1 family core complex shows that in the absence of WRAD all SET domains catalyze at least weak H3K4 monomethylation; in the presence of WRAD, all SET1 family members show stimulated monomethyltransferase activity but differ in di- and trimethylation activities correlated with evolutionary lineage; phylogenetic scanning mutagenesis identified a cluster of residues that confer WRAD-dependent gain-of-function dimethylation activity.","method":"Biochemical reconstitution of core complexes, in vitro methyltransferase assays, phylogenetic mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic biochemical reconstitution of all SET1 family complexes including SETd1A with mutagenesis","pmids":["25561738"],"is_preprint":false},{"year":2015,"finding":"SET1 (SETD1A) mediates H3K4me3 accumulation at the endothelin-1 (EDN1) promoter in endothelial cells upon angiotensin II stimulation; SET1 is recruited to the EDN1 promoter by AP-1 (c-Jun/c-Fos) and synergizes with AP-1 to activate transcription; endothelial-specific deletion of SET1 in mice attenuates Ang II-induced cardiac hypertrophy and fibrosis.","method":"ChIP, Co-IP, siRNA knockdown, conditional knockout mice, cardiomyocyte hypertrophy assay","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + Co-IP + in vivo KO with physiological phenotype, single lab","pmids":["25814673"],"is_preprint":false},{"year":2016,"finding":"Mutation of the Win motif-WDR5 interface severely disrupts assembly and activity of MLL1 and SETd1A complexes but only modestly disrupts MLL2/4 and SETd1B complexes; a peptidomimetic targeting the Win motif-WDR5 interaction selectively inhibits MLL1 and SETd1A core complex activity within the SET1 family.","method":"Biochemical reconstitution, in vitro methyltransferase assay, Win motif mutagenesis, peptide inhibitor design and enzymatic assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic reconstitution with mutagenesis and selective inhibitor, multiple SET1 family members compared","pmids":["27563068"],"is_preprint":false},{"year":2016,"finding":"Among SET1/MLL family H3K4 methyltransferases, Set1a specifically interacts with Oct4; this interaction is independent of Wdr5; Set1a is recruited to and required for H3K4 methylation at Oct4 target gene promoters; Set1a is required for ES cell maintenance, iPSC generation, and generation of Oct4-positive inner cell mass.","method":"Co-immunoprecipitation, ChIP, ChIP-seq, gene knockout, gene expression profiling","journal":"Stem cells","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP defining specific Oct4-Set1a interaction, ChIP-seq for genome-wide binding, KO with developmental phenotype, multiple orthogonal methods","pmids":["26785054"],"is_preprint":false},{"year":2017,"finding":"The vertebrate SET1 complex is targeted to actively transcribed gene promoters through CFP1, which engages in multivalent chromatin reading involving recognition of non-methylated CpG DNA and H3K4me3; CFP1 defines SET1 complex occupancy on chromatin and its multivalent interactions are required for the SET1 complex to place H3K4me3; loss of CFP1 perturbs gene expression.","method":"Live-cell imaging, functional genomics (ChIP-seq), CFP1 point mutant analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — live imaging plus genome-wide ChIP-seq plus domain mutagenesis, multiple orthogonal methods","pmids":["28877467"],"is_preprint":false},{"year":2017,"finding":"Nup98 binds predominantly to transcription start sites in hematopoietic cells and recruits the Wdr82-Set1A/COMPASS complex, which is required for H3K4me3 deposition; depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and abrogates H3K4me3 at adjacent promoters; AML-associated Nup98 fusion protein causes mislocalization of H3K4me3.","method":"ChIP-seq, siRNA knockdown, co-immunoprecipitation, protein localization","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq + RNAi + Co-IP establishing mechanistic pathway of Nup98→Wdr82→Set1A→H3K4me3","pmids":["29269482"],"is_preprint":false},{"year":2017,"finding":"Set1 complex directly binds RNA in vitro through the double RRM and N-SET domain of Set1 and through its subunit Spp1; RNA binding (CRAC assay) shows Set1 binds nascent transcripts near transcription start sites; RNA binding is important for appropriate topology of Set1C distribution along transcription units and correlates with efficient H3K4me3 deposition; Set1 also binds non-nascent RNAs including Ty1 retrotransposons and its own mRNA.","method":"In vitro RNA binding assay, UV RNA crosslinking (CRAC), ChIP-seq, parallel analysis of RNAPII binding","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus in vivo CRAC crosslinking, single lab","pmids":["29071121"],"is_preprint":false},{"year":2018,"finding":"SET1A mediates mono-methylation of YAP at K342, which disrupts YAP's binding to CRM1 and blocks its nuclear export, thereby sequestering active YAP in the nucleus; YAP K342 methylation knockin mice are more susceptible to colorectal tumorigenesis.","method":"In vitro methylation assay, co-immunoprecipitation, nuclear export assay, knockin mouse model, mutagenesis","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro methylation of non-histone substrate (YAP K342) plus co-IP for CRM1 interaction plus in vivo knockin mouse, multiple orthogonal methods","pmids":["30008322"],"is_preprint":false},{"year":2018,"finding":"SETD1A has an essential non-catalytic function through a newly identified 'FLOS' domain that acts as a cyclin-K-binding site; FLOS disruption suppresses DNA damage response genes and induces p53-dependent apoptosis in AML cells; the FLOS domain is required for chromosomal recruitment of cyclin K and DNA-repair-associated gene expression in S phase; the enzymatic SET domain is not necessary for AML cell survival.","method":"CRISPR-Cas9 domain screening, mutagenesis studies, co-immunoprecipitation (SETD1A-cyclin K), ChIP, apoptosis assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR domain screen + mutagenesis + Co-IP + ChIP, published in Cell, identifies non-catalytic function with defined binding partner","pmids":["29474905"],"is_preprint":false},{"year":2018,"finding":"SETD1A catalyzes H3K4 methylation at stalled replication forks, which enhances FANCD2-dependent histone chaperone activity; depletion of SETD1A leads to DNA2-dependent resection of damaged replication forks; suppressing H3K4 methylation or expression of a chaperone-defective FANCD2 mutant leads to loss of RAD51 nucleofilament stability and nucleolytic fork degradation.","method":"Depletion/siRNA of SETD1A, fork degradation assays, H3K4 methylation ChIP at replication forks, FANCD2 chaperone mutant analysis, RAD51 foci","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — depletion with specific molecular phenotype, epistasis with FANCD2 chaperone mutant, multiple readouts linking SETD1A H3K4me to fork protection","pmids":["29937342"],"is_preprint":false},{"year":2018,"finding":"Uhrf1 forms a complex with Setd1a/COMPASS to maintain bivalent H3K4me3/H3K27me3 histone marks in ES cells, particularly those associated with neuroectoderm and mesoderm specification.","method":"Co-immunoprecipitation, ChIP-seq, knockdown of Uhrf1","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying complex plus ChIP-seq for genome-wide histone marks, single lab","pmids":["29968706"],"is_preprint":false},{"year":2018,"finding":"SETD1A is recruited to the THBD (thrombomodulin) promoter by the transcription factor KLF4 in response to retinoic acid; SETD1A also mediates H3K4me3-dependent upregulation of KLF4 expression via retinoic acid receptor; SETD1A knockdown reduces H3K4me3 at the THBD promoter and blocks retinoic acid-induced thrombomodulin transcription.","method":"ChIP, Co-IP, siRNA knockdown, reporter assay","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + Co-IP + KD with functional readout, single lab","pmids":["29940355"],"is_preprint":false},{"year":2018,"finding":"SETD1A protects hematopoietic stem cells (HSCs) from activation-induced functional decline; conditional deletion of Setd1a in adult LT-HSCs is compatible with steady-state hematopoiesis but causes loss of transcriptional cellular identity, proliferative capacity, and stem cell function under replicative stress or after transplantation; SETD1A regulates expression of DNA damage recognition and repair pathways in HSCs.","method":"Conditional gene knockout (Setd1a-cKO in LT-HSCs), transplantation assays, RNA-seq, ChIP","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with defined functional phenotypes (transplantation, replicative stress), transcriptome analysis, single lab","pmids":["29348130"],"is_preprint":false},{"year":2019,"finding":"Setd1a heterozygous loss-of-function mice exhibit axonal branching defects, altered cortical synaptic dynamics, and working memory deficits; Setd1a binds both promoters and enhancers with striking overlap with Mef2 on enhancers; LSD1 is identified as a major counteracting demethylase for Setd1a; pharmacological inhibition of LSD1 rescues behavioral and morphological deficits in Setd1a-deficient mice.","method":"Heterozygous mouse model (Setd1a+/-), ChIP-seq for Setd1a binding, morphological analysis of axons, behavioral testing, LSD1 inhibitor treatment","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq + in vivo mouse model with morphological and behavioral phenotypes + pharmacological rescue identifying LSD1 as counteracting demethylase, multiple orthogonal methods","pmids":["31606247"],"is_preprint":false},{"year":2020,"finding":"The Set1 N-terminal region and COMPASS subunit Swd2 interact with each other and are both needed for efficient Pol II CTD binding; a single point mutation in Swd2 that affects its interaction with Set1 impairs COMPASS recruitment to chromatin and H3K4 methylation; H2B ubiquitylation is still required for efficient H3K4 methylation even when Set1/COMPASS is recruited via an alternative CTD interaction domain (Nrd1 CID), indicating H2Bub acts after initial COMPASS recruitment.","method":"Co-immunoprecipitation, CTD pulldown assays, point mutagenesis of Swd2, ChIP, domain swap experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple Co-IP experiments + domain mutagenesis + ChIP establishing the Set1 N-terminal/Swd2 dual CTD-binding mechanism, single lab but multiple orthogonal methods","pmids":["32358498"],"is_preprint":false},{"year":2020,"finding":"SETD1A interacts with HIF1α and co-occupies the promoters of glycolytic genes (HK2, PFK2); SETD1A methylates H3K4 at these promoters to strengthen HIF1α transactivation; knockdown of SETD1A reduces H3K4 methylation at HK2 and PFK2 promoters, reduces HIF1α recruitment, and decreases glycolytic gene expression and glycolysis.","method":"Co-immunoprecipitation (SETD1A-HIF1α), ChIP (SETD1A and H3K4me3), siRNA knockdown, metabolic assays","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + ChIP + functional KD, single lab","pmids":["32291851"],"is_preprint":false},{"year":2020,"finding":"Setd1a haploinsufficiency in mice causes highly variable transcriptional adaptations across different cell types in prefrontal cortex and striatum; Foxp2+ neurons show the most prominent gene expression changes that correlate with changes in H3K4me3; dysregulated genes involve neuron morphogenesis and synaptic function.","method":"Single-cell RNA sequencing in Setd1a+/- mice, H3K4me3 ChIP-seq, behavioral assays","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNA-seq + ChIP-seq in mouse model, single lab","pmids":["35245111"],"is_preprint":false},{"year":2020,"finding":"Setd1a knockdown in layer 2/3 pyramidal neurons of the medial prefrontal cortex specifically recapitulates impaired sociality; postsynaptic Setd1a is essential for excitatory synaptic transmission as demonstrated by optogenetics-assisted selective stimulation of presynaptic neurons combined with Setd1a RNAi knockdown.","method":"Conditional Setd1a knockdown by RNAi in specific neurons, optogenetics, electrophysiology, behavioral assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KD with optogenetics-assisted electrophysiology, single lab","pmids":["32937141"],"is_preprint":false},{"year":2021,"finding":"SETD1A interacts with and stabilizes β-catenin (through a SET-domain-independent mechanism) to positively regulate the Wnt/β-catenin pathway; SETD1A also binds to the promoters of NEAT1 and EZH2 to activate transcription via H3K4me3 enrichment, contributing to cancer stem cell properties; a positive feedback loop exists where SETD1A is a direct target of the Wnt/β-catenin pathway.","method":"Co-immunoprecipitation (SETD1A-β-catenin), ChIP, luciferase reporter, SET domain deletion mutant analysis","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP + ChIP + reporter assays, single lab, SET domain deletion is partial mechanistic follow-up","pmids":["34645486"],"is_preprint":false},{"year":2022,"finding":"H3K4 methylation by SETD1A-BOD1L facilitates recruitment of RIF1 to DSBs; RIF1 directly binds methylated H3K4; compromising SETD1A or BOD1L expression impairs RIF1 localization to DSBs, leads to uncontrolled DNA end resection, impairs telomere end-joining and class switch recombination; patient cells with SETD1A loss-of-function mutations show RIF1 localization defects; loss of SETD1A-dependent RIF1 recruitment in BRCA1-deficient cells restores homologous recombination.","method":"Co-immunoprecipitation, RIF1 foci assays, DNA end-joining assays (telomere FISH, class switch recombination), patient cell lines with SETD1A LoF, BRCA1-deficient cell epistasis, direct binding assay (RIF1 to H3K4me peptides)","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct RIF1-H3K4me binding assay + functional epistasis in multiple cell systems including patient cells + multiple DNA repair readouts, single lab but comprehensive","pmids":["35439434"],"is_preprint":false},{"year":2022,"finding":"SETD1A haploinsufficiency in human iPSC-derived excitatory/inhibitory neuronal networks results in increased dendritic complexity and increased network bursting activity; perturbations in glutamatergic synaptic function genes and hyperactive cAMP/PKA pathway were identified; pharmacological targeting of the cAMP pathway rescues the network deficits.","method":"CRISPR-Cas9 SETD1A+/- iPSC-derived neurons, multi-electrode array, transcriptomics, cAMP pathway pharmacological rescue","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human iPSC model with electrophysiology + transcriptomics + pharmacological rescue identifying cAMP/PKA as downstream pathway, single lab","pmids":["35508131"],"is_preprint":false}],"current_model":"SETD1A is the catalytic subunit of a conserved multi-protein COMPASS complex (containing WDR5, RbBP5, ASH2L, DPY30, Wdr82, CFP1, and HCF-1 among others) that primarily trimethylates histone H3 at lysine 4 (H3K4me3) at transcription start sites through co-transcriptional recruitment via Wdr82 binding to the Ser5-phosphorylated Pol II CTD; its methyltransferase activity is stimulated by H2B ubiquitylation (which promotes processivity from mono- to trimethylation) and regulated by an n-SET domain crosstalk mechanism; beyond H3K4, SETD1A monomethylates the non-histone substrate YAP at K342 to block its nuclear export, and its non-catalytic FLOS domain recruits cyclin K to regulate DNA damage response gene expression; SETD1A-dependent H3K4 methylation at replication forks protects nascent DNA from resection via FANCD2 chaperone activity and recruits RIF1 to DSBs to promote NHEJ; in neurons, SETD1A haploinsufficiency disrupts excitatory synaptic function and axonal branching, with LSD1 acting as the primary counteracting demethylase whose inhibition rescues behavioral deficits."},"narrative":{"mechanistic_narrative":"SETD1A is the catalytic subunit of a conserved multi-protein COMPASS/Set1 complex that deposits histone H3 lysine 4 methylation, the dominant H3K4 methyltransferase activity in eukaryotic cells [PMID:11751634, PMID:11742990, PMID:16253997]. Within the complex, the WRAD module (WDR5, RbBP5, ASH2L, DPY30) and the Win-motif/WDR5 interface are required for assembly and for stimulating SETD1A's progression from mono- to di- and trimethylation, while a Phe/Tyr switch and the n-SET domain govern trimethyltransferase output and read H2B ubiquitylation crosstalk that controls processivity [PMID:22266653, PMID:25561738, PMID:27563068, PMID:23453808, PMID:16039595]. The complex is targeted to active promoters and transcription start sites co-transcriptionally: Wdr82 and the Set1 N-terminal/Swd2 module bind the Ser5-phosphorylated Pol II CTD, CFP1 reads non-methylated CpG DNA and H3K4me3, and recruitment is further directed by Nup98, TET/OGT-modified HCF-1, and sequence-specific factors including p53, Oct4, KLF4, HIF1α, and AP-1 [PMID:17998332, PMID:32358498, PMID:28877467, PMID:29269482, PMID:23353889, PMID:23870121, PMID:26785054]. Beyond chromatin, SETD1A monomethylates the non-histone substrate YAP at K342 to block CRM1-dependent nuclear export and, through its non-catalytic FLOS domain, recruits cyclin K to drive DNA-damage-response gene expression independently of its SET domain [PMID:30008322, PMID:29474905]. At the genome, SETD1A-dependent H3K4 methylation protects stalled replication forks via FANCD2 chaperone activity and recruits RIF1 to double-strand breaks to bias repair toward end-joining [PMID:29937342, PMID:35439434]. SETD1A is essential for embryonic development, pluripotency, and hematopoietic stem cell maintenance, and its haploinsufficiency disrupts excitatory synaptic function, dendritic and axonal morphology, and behavior, with the demethylase LSD1 acting as a counteracting eraser whose inhibition rescues these deficits [PMID:24550110, PMID:29348130, PMID:31606247, PMID:35508131].","teleology":[{"year":2001,"claim":"Established that Set1/SETD1A is itself an enzyme and the principal cellular source of H3K4 methylation, and that it acts within a defined multi-subunit complex rather than alone.","evidence":"Genetic deletion with complementation rescue in yeast and Co-IP/MS identification of the eight-subunit Set1C/COMPASS","pmids":["11751634","11742990"],"confidence":"High","gaps":["Does not define how the complex is targeted to specific genes","Subunit functions within the complex not yet assigned"]},{"year":2003,"claim":"Resolved how the complex is delivered to active genes by linking Set1 recruitment to the transcribing polymerase, defining co-transcriptional deposition of H3K4me.","evidence":"ChIP, Co-IP and genetic epistasis showing Set1 binds the Ser5-phosphorylated Pol II CTD and depends on Paf1/CTD kinase; human Set1/Ash2 shown to methylate H3K4 and to be tethered with HCF-1","pmids":["12667453","12670868"],"confidence":"High","gaps":["Direct CTD-binding subunit not yet identified","Does not explain control of methylation degree"]},{"year":2005,"claim":"Defined the determinants of methylation degree and substrate breadth, showing H2B ubiquitylation, the Set1 N-terminus, and an RRM control mono-versus-trimethylation, and that Set1 can methylate a non-histone kinetochore substrate.","evidence":"Genetic H2B-K123 mutation, N-terminal mutagenesis, RRM1 crystal structure/RNA binding, CFP1 identification, and in vitro methylation of Dam1 with ipl1-2 suppressor analysis","pmids":["16039595","15964832","15775977","16253997","16143104"],"confidence":"High","gaps":["Mechanism coupling H2Bub to processivity not yet structural","Generality of non-histone methylation to mammalian SETD1A untested at this stage"]},{"year":2007,"claim":"Identified Wdr82 as the CTD-binding adaptor specific to Set1A/B complexes, mechanistically explaining how SETD1A (not MLL complexes) is positioned at transcription start sites.","evidence":"Co-IP, peptide binding to Ser5-phospho CTD, ChIP and siRNA knockdown; AP-MS confirming Wdr82 as Set1-specific","pmids":["17998332","18838538","17578910"],"confidence":"High","gaps":["Does not address DNA-sequence-level targeting","Relative contribution of Wdr82 versus other adaptors unresolved"]},{"year":2009,"claim":"Dissected complex architecture and catalytic chemistry, assigning subunit roles in stability and trimethylation and placing H3K4me2 upstream of deacetylase recruitment and elongation.","evidence":"Subunit deletion/Co-IP, structure-guided Tyr1052 mutagenesis, and PHD-finger binding linking H3K4me2 to Set3C recruitment","pmids":["16921172","19398585","19379692"],"confidence":"High","gaps":["Catalytic-state transitions not captured structurally","Downstream readers of H3K4me3 in this context not defined"]},{"year":2012,"claim":"Defined the WDR5-Win motif interface as the assembly hub that licenses SETD1A catalytic stimulation by RbBP5-ASH2L.","evidence":"Crystal structures of WDR5-Win complexes plus in vitro methyltransferase assays","pmids":["22266653"],"confidence":"High","gaps":["Does not establish in-cell dependence of SETD1A on this interface"]},{"year":2013,"claim":"Connected SETD1A targeting to upstream signaling and chromatin context, showing p53/p300 acetylation, TET/OGT-modified HCF-1, and the n-SET/H2Bub crosstalk module direct and license its activity.","evidence":"In vitro reconstitution on recombinant chromatin, Co-IP, ChIP, MS-PTM identification of HCF1 GlcNAcylation, and n-SET domain reconstitution extended to the human complex","pmids":["23870121","23353889","23453808","23508102"],"confidence":"High","gaps":["Quantitative hierarchy among these recruitment cues unknown","How signaling switches between targets not resolved"]},{"year":2014,"claim":"Established SETD1A as developmentally essential and non-redundant with SETD1B, tying its H3K4 methyltransferase activity to pluripotency and proliferation.","evidence":"Conditional mouse knockout, ES cell deletion with H3K4me loss and G1 arrest, and failed Setd1b rescue","pmids":["24550110"],"confidence":"High","gaps":["Molecular basis of SETD1A/SETD1B non-redundancy not defined","Direct target genes driving proliferation arrest not enumerated"]},{"year":2016,"claim":"Refined targeting and selectivity, showing CFP1 multivalent chromatin reading and Oct4-specific recruitment define SETD1A occupancy, and that the Win-WDR5 interface is selectively required for SETD1A among the family.","evidence":"Live imaging, ChIP-seq, CFP1 point mutants, Oct4 Co-IP/ChIP-seq, and Win-motif peptidomimetic inhibition","pmids":["28877467","26785054","27563068"],"confidence":"High","gaps":["Interplay between CFP1 reading and transcription-factor recruitment unresolved","Selective inhibitor effects on non-catalytic functions untested"]},{"year":2018,"claim":"Uncovered catalytic and non-catalytic functions beyond promoter H3K4me3: monomethylation of YAP to control its localization, a FLOS domain that recruits cyclin K, and roles protecting replication forks via FANCD2.","evidence":"In vitro methylation and nuclear export assays with YAP knockin mice; CRISPR domain screen, mutagenesis and SETD1A-cyclin K Co-IP; fork degradation and FANCD2 chaperone-mutant analysis","pmids":["30008322","29474905","29937342","29968706","29940355","29348130"],"confidence":"High","gaps":["Full non-histone substrate repertoire unknown","Separation of catalytic versus FLOS-domain contributions in normal tissues unclear"]},{"year":2019,"claim":"Defined the neuronal consequences of SETD1A haploinsufficiency and identified LSD1 as the counteracting demethylase, providing a pharmacologically tractable axis.","evidence":"Setd1a+/- mice with ChIP-seq, axonal/synaptic morphology, behavior, and LSD1 inhibitor rescue","pmids":["31606247"],"confidence":"High","gaps":["Causal target genes mediating behavioral phenotypes not pinpointed","Cell-type specificity of LSD1 antagonism not fully mapped"]},{"year":2020,"claim":"Mechanistically extended recruitment and CTD-engagement models and dissected cell-type-specific transcriptional and synaptic effects of haploinsufficiency.","evidence":"Swd2/Set1 N-terminal CTD-binding mutagenesis with ChIP; scRNA-seq and H3K4me3 ChIP-seq in Setd1a+/- mice; cell-type-specific RNAi with optogenetics-electrophysiology; HIF1α Co-IP/ChIP at glycolytic promoters","pmids":["32358498","35245111","32937141","32291851"],"confidence":"High","gaps":["How a single mark produces variable cell-type adaptations unresolved","Direct link from glycolytic-gene regulation to organismal phenotypes untested"]},{"year":2022,"claim":"Established a direct H3K4-methyl reader axis in DNA repair and a translatable downstream pathway in neurons, showing RIF1 binds SETD1A/BOD1L-deposited H3K4me to bias end-joining, and that cAMP/PKA hyperactivity underlies network deficits in patient-derived neurons.","evidence":"Direct RIF1-H3K4me peptide binding, end-joining and BRCA1 epistasis assays in patient cells; SETD1A+/- iPSC neurons with multi-electrode arrays, transcriptomics, and cAMP pathway rescue","pmids":["35439434","35508131"],"confidence":"High","gaps":["Whether the same axis operates at endogenous DSBs genome-wide unsettled","Link between repair function and neuropsychiatric phenotype not established"]},{"year":null,"claim":"How SETD1A's distinct activities — promoter H3K4me3, non-histone methylation, FLOS-mediated cyclin K recruitment, fork protection, and DSB repair — are partitioned and prioritized within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model integrating catalytic and non-catalytic functions","Determinants selecting among competing targets unknown","Substrate specificity rules for non-histone methylation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3,4,23,30]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[7,30]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[18,27]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[8,29]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[19,26,38]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,15]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3,19,27]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,10,19,27]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[4,18,27,33]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[31,32,42]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[21,26,36]}],"complexes":["COMPASS/Set1 complex","kinetochore (Dam1 substrate)"],"partners":["WDR5","CFP1/CXXC1","WDR82","HCF-1","RBBP5","ASH2L","RIF1","CYCLIN K"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15047","full_name":"Histone-lysine N-methyltransferase SETD1A","aliases":["Lysine N-methyltransferase 2F","SET domain-containing protein 1A","hSET1A","Set1/Ash2 histone methyltransferase complex subunit SET1"],"length_aa":1707,"mass_kda":186.0,"function":"Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of 'Lys-4' of histone H3 (H3K4) via a non-processive mechanism (PubMed:12670868, PubMed:25561738). Part of chromatin remodeling machinery, forms H3K4me1, H3K4me2 and H3K4me3 methylation marks at active chromatin sites where transcription and DNA repair take place (PubMed:29937342, PubMed:31197650, PubMed:32346159). Responsible for H3K4me3 enriched promoters and transcriptional programming of inner mass stem cells and neuron progenitors during embryogenesis (By similarity) (PubMed:31197650). Required for H3K4me1 mark at stalled replication forks. Mediates FANCD2-dependent nucleosome remodeling and RAD51 nucleofilaments stabilization at reversed forks, protecting them from nucleolytic degradation (PubMed:29937342, PubMed:32346159). Does not methylate 'Lys-4' of histone H3 if the neighboring 'Lys-9' residue is already methylated (PubMed:12670868). Binds RNAs involved in RNA processing and the DNA damage response (PubMed:38003223)","subcellular_location":"Nucleus speckle; Chromosome; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O15047/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SETD1A","classification":"Common Essential","n_dependent_lines":1144,"n_total_lines":1208,"dependency_fraction":0.9470198675496688},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SETD1A","total_profiled":1310},"omim":[{"mim_id":"619056","title":"NEURODEVELOPMENTAL DISORDER WITH SPEECH IMPAIRMENT AND DYSMORPHIC FACIES; NEDSID","url":"https://www.omim.org/entry/619056"},{"mim_id":"618832","title":"EPILEPSY, EARLY-ONSET, 2, WITH OR WITHOUT DEVELOPMENTAL DELAY; EPEO2","url":"https://www.omim.org/entry/618832"},{"mim_id":"617290","title":"EPILEPSY, EARLY-ONSET, 1, VITAMIN B6-DEPENDENT; EPEO1","url":"https://www.omim.org/entry/617290"},{"mim_id":"611055","title":"SET DOMAIN-CONTAINING PROTEIN 1B; SETD1B","url":"https://www.omim.org/entry/611055"},{"mim_id":"611052","title":"SET DOMAIN-CONTAINING PROTEIN 1A; SETD1A","url":"https://www.omim.org/entry/611052"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SETD1A"},"hgnc":{"alias_symbol":["KIAA0339","Set1","KMT2F","SET1A"],"prev_symbol":[]},"alphafold":{"accession":"O15047","domains":[{"cath_id":"-","chopping":"15-63","consensus_level":"medium","plddt":62.2904,"start":15,"end":63},{"cath_id":"3.30.70.330","chopping":"96-197","consensus_level":"high","plddt":90.576,"start":96,"end":197},{"cath_id":"2.170.270.10","chopping":"1563-1599_1641-1707","consensus_level":"medium","plddt":89.785,"start":1563,"end":1707}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15047","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15047-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15047-F1-predicted_aligned_error_v6.png","plddt_mean":48.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SETD1A","jax_strain_url":"https://www.jax.org/strain/search?query=SETD1A"},"sequence":{"accession":"O15047","fasta_url":"https://rest.uniprot.org/uniprotkb/O15047.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15047/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15047"}},"corpus_meta":[{"pmid":"12667453","id":"PMC_12667453","title":"Targeted 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deletion of SET1 abolishes all H3K4 methylation in vivo, and this can be rescued by re-expression of SET1.\",\n      \"method\": \"Genetic deletion, in vivo histone methylation assay with methyl-specific antiserum, complementation rescue\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vivo enzymatic loss-of-function with rescue, independently replicated across multiple labs\",\n      \"pmids\": [\"11751634\", \"11742990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Set1 exists as an eight-subunit complex (Set1C/COMPASS), which includes an Ash2/Bre2 homologue; complex integrity requires Set1, and loss of Set1 disrupts the complex.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, biochemical fractionation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP + MS, replicated across multiple labs and organisms\",\n      \"pmids\": [\"11742990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Set1 is recruited to the 5' portion of active mRNA coding regions by the Pol II elongation machinery; Set1 physically interacts with the Ser5-phosphorylated (but not Ser2-phosphorylated) form of the Pol II CTD, and its recruitment depends on the TFIIH-associated CTD kinase and on Rtf1/Paf1 components of the Paf1 complex.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), co-immunoprecipitation, genetic epistasis with CTD kinase and Paf1 complex mutants\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP + Co-IP + genetic epistasis, replicated in multiple studies\",\n      \"pmids\": [\"12667453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human Set1/Ash2 histone methyltransferase complex (containing SETD1A) methylates histone H3 at Lys4 but not if the neighboring K9 residue is already methylated; HCF-1 tethers this Set1/Ash2 HMT complex together with the Sin3 HDAC complex, and the transcriptional activator VP16 selectively binds HCF-1 associated with Set1/Ash2 in the absence of Sin3.\",\n      \"method\": \"In vitro histone methyltransferase assay, co-immunoprecipitation, domain mapping\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with substrate specificity analysis plus reciprocal Co-IP, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"12670868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human CFP1 (CXXC finger protein 1) is a component of the mammalian SETD1A/Set1 complex; the complex produces mono-, di-, and trimethylated H3K4 in vitro; CFP1 and SETD1A co-localize to nuclear speckles associated with euchromatin; cells lacking CFP1 show elevated H3K4 methylation, indicating CFP1 restricts SETD1A activity.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, in vitro methyltransferase assay, confocal microscopy, genetic knockout of CFP1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro activity, Co-IP/MS subunit identification, live imaging localization, loss-of-function phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"16253997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"H2B ubiquitylation at K123 is dispensable for monomethylation of H3K4 by Set1 but is required for the transition from monomethylation to di- and trimethylation (processive methylation); Dot1 binding to chromatin is normal without H2Bub, suggesting ubiquitylation regulates processivity rather than recruitment.\",\n      \"method\": \"Chromatin immunoprecipitation, mass spectrometry, genetic mutation of H2B K123\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP + MS distinguishing mono/di/trimethylation states, genetic epistasis, replicated concept in multiple papers\",\n      \"pmids\": [\"16039595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The N-terminal region of Set1 is required for global H3K4 trimethylation; Set1 trimethyl-defective N-terminal mutants are defective in telomere, rDNA, HML, and HMR silencing, while mono- and/or dimethylation by Set1 is sufficient for cell growth.\",\n      \"method\": \"Yeast genetics, site-directed mutagenesis, chromatin immunoprecipitation, silencing assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mutagenesis with silencing and growth phenotype readouts, single lab\",\n      \"pmids\": [\"15964832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Set1 methyltransferase is required for methylation of conserved lysines in the kinetochore protein Dam1; Dam1 methylation by Set1 inhibits Ipl1 Aurora kinase-mediated phosphorylation of flanking serines, with SET1 deletion suppressing chromosome loss in ipl1-2 cells; this function is independent of Set1's role in H3K4 methylation and transcription.\",\n      \"method\": \"Genetic epistasis (suppressor analysis of ipl1-2), biochemical methylation assay of Dam1, genetic double-mutant analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis + in vitro methylation of non-histone substrate + functional rescue, published in Cell, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"16143104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The RNA recognition motif 1 (RRM1) of Set1, when combined with a newly identified RRM2, specifically binds RNA in vitro; RRM1 mutation destabilizes Set1 and alters the ratio of H3K4 di- to trimethylation at active genes, reducing trimethylation while increasing dimethylation at 5'-coding regions.\",\n      \"method\": \"Crystal structure of RRM1, RNA-binding assay in vitro, in vivo H3K4 methylation analysis by ChIP, site-directed mutagenesis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus in vitro binding assay plus in vivo functional mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15775977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Within the Set1 complex, Swd1 and Swd3 are required for complex integrity and Set1 stability; the Bre2-Sdc1 heterodimer is required for H3K4 trimethylation at the 5' end of active genes; Set1C associates with both Ser5- and Ser2-phosphorylated forms of Pol II, indicating persistent association throughout transcription.\",\n      \"method\": \"Co-immunoprecipitation, genetic deletion of individual subunits, western blot for Set1 levels, ChIP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic protein interaction mapping within the complex combined with in vivo chromatin analysis, multiple genetic deletions\",\n      \"pmids\": [\"16921172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The Wdr82 component of the human SETD1A complex interacts with the RNA recognition motif of SETD1A and binds to the Ser5-phosphorylated CTD of RNA Pol II (but not unphosphorylated or Ser2-phosphorylated CTD); siRNA depletion of Wdr82 decreases SETD1A expression and its occupancy at transcription start sites and reduces H3K4me3 at those sites, without altering Pol II occupancy or target gene expression.\",\n      \"method\": \"Co-immunoprecipitation, peptide binding assays, chromatin immunoprecipitation, siRNA knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP, functional KD with multiple readouts, mechanistically defines Wdr82 as CTD-binding adaptor for SETD1A\",\n      \"pmids\": [\"17998332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HCF-1 recruits SETD1A (Set1) and MLL1 histone methyltransferases to herpesvirus immediate early promoters, leading to H3K4me3 and transcriptional activation; HCF-1 is required for this chromatin modification step but not for assembly of the basal RNAPII complex.\",\n      \"method\": \"ChIP at viral promoters, epistasis with HCF-1, promoter reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with functional epistasis on viral promoters, single lab\",\n      \"pmids\": [\"17578910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Wdr82 is a specific component of the human Set1A/B complexes but not MLL1-4 complexes; siRNA knockdown of Wdr82 reduces H3K4 trimethylation levels in vivo; in vitro, the Set1 complex is a more robust H3K4 trimethylase than MLL complexes.\",\n      \"method\": \"Affinity purification/mass spectrometry, RNAi knockdown, in vitro histone methyltransferase assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic reconstitution combined with in vivo RNAi and AP-MS, multiple orthogonal methods\",\n      \"pmids\": [\"18838538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Tyr1052 (the Phe/Tyr switch) in the catalytic domain of Set1 is essential for H3K4 trimethylation by COMPASS; mutation Y1052F suppresses the trimethylation defect caused by loss of Cps40/Spp1, but does not suppress defects from loss of H2B monoubiquitination, indicating Tyr1052 and Cps40 function together downstream of and independently of H2Bub.\",\n      \"method\": \"Homology modeling, site-directed mutagenesis, in vivo H3K4 methylation analysis, ChIP\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structure-guided mutagenesis with in vivo functional readouts, single lab\",\n      \"pmids\": [\"19398585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"H3K4 dimethylation by Set1 recruits the Set3 histone deacetylase complex via the Set3 PHD finger to 5' transcribed regions, where Hos2 and Hst1 deacetylate histones; this reduces histone acetylation near 5' ends of genes and positively affects transcription elongation.\",\n      \"method\": \"Genetic epistasis, ChIP, PHD finger binding assay, growth assays on mycophenolic acid\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis + ChIP + domain binding, published in Cell, mechanistic pathway placed Set1→H3K4me2→Set3C recruitment\",\n      \"pmids\": [\"19379692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CFP1 restricts the SETD1A complex to euchromatin; in CFP1-null ES cells, SETD1A and H3K4me3 mislocalize to heterochromatin; both the DNA-binding activity of CFP1 and its interaction with the SETD1A complex are required for proper SETD1A genomic targeting.\",\n      \"method\": \"Confocal microscopy, genetic knockout (CXXC1-/-), structure-function analysis of CFP1 point mutations and truncations\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization by imaging tied to functional consequence, structure-function mutagenesis, single lab\",\n      \"pmids\": [\"19951360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"WDR5 binds the Win (WDR5-interacting) motifs of MLL2-4, SET1A, and SET1B; crystal structures of WDR5-Win complexes show binding is achieved by plasticity of WDR5's peptidyl-arginine-binding cleft; WDR5 is important for optimal stimulation of SET1A methyltransferase activity by the RbBP5-ASH2L heterodimer.\",\n      \"method\": \"Crystal structure determination, biochemical binding assays, in vitro methyltransferase assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures plus enzymatic activity assays, mechanistically defines WDR5 role in SET1A complex assembly\",\n      \"pmids\": [\"22266653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TET2 and TET3 directly interact with OGT; TET2/3-OGT co-localize on chromatin at H3K4me3-enriched active promoters; reduction of TET2/3 or OGT activity decreases H3K4me3 and transcription; HCF1, a SET1/COMPASS component, is a specific GlcNAcylation target of TET2/3-OGT, and HCF1 modification is important for COMPASS integrity; TET proteins and OGT promote chromatin binding of SETD1A.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, OGT activity assays, knockdown of TET2/3 and OGT, mass spectrometry identification of HCF1 GlcNAcylation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, enzymatic assay, MS-PTM identification), single lab but comprehensive\",\n      \"pmids\": [\"23353889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The n-SET domain of Set1 (but not Swd2) is essential for H2Bub-dependent H3K4 methylation on reconstituted chromatin templates; Spp1 (CFP1 homolog) is conditionally involved in this crosstalk; this mechanism is conserved in the human Set1 complex.\",\n      \"method\": \"In vitro histone methyltransferase assay with reconstituted yeast Set1 complex and fully ubiquitylated H2B chromatin template, n-SET domain mutagenesis, genetic analyses\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution on chromatin template with mutagenesis, extended to human complex, single lab\",\n      \"pmids\": [\"23453808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In vitro studies with recombinant chromatin and purified human SET1 complex (SET1C) show robust H3K4me3 that is dependent on p53/p300-mediated H3 acetylation; SET1C directly interacts with p53 and p300; DNA-damage induces p53-SET1C interaction in cells with enrichment of SET1C and H3K4me3 at the p21/WAF1 promoter; H3K4me3 and transcription codepend on both SET1C and p300.\",\n      \"method\": \"In vitro transcription/methylation assay with recombinant chromatin, Co-IP, ChIP, cell-based assays with DNA damage\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution on recombinant chromatin plus Co-IP plus ChIP in cells, multiple orthogonal methods, published in Cell\",\n      \"pmids\": [\"23870121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Quantitative mass spectrometry revealed Bod1 protein as a discriminator between SET1B and SET1A complexes, distinguishing their subunit composition; DPY30 is a genuine subunit of both SET1/MLL complexes and the NURF chromatin remodeling complex.\",\n      \"method\": \"Label-free quantitative mass spectrometry, affinity purification\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative AP-MS with stoichiometry determination, single lab\",\n      \"pmids\": [\"23508102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mouse Setd1a is required for gastrulation; Setd1a knockout embryos implant but fail to progress past the epiblast stage; deletion of Setd1a in ES cells causes rapid loss of bulk H3K4 methylation, pluripotency gene expression, and proliferation with G1 arrest; Setd1b overexpression cannot rescue the proliferation defects caused by Setd1a loss.\",\n      \"method\": \"Conditional gene knockout in mice, ES cell deletion, western blot for H3K4 methylation, flow cytometry for cell cycle\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular and developmental phenotypes, multiple readouts, single lab\",\n      \"pmids\": [\"24550110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SETD1A suppresses BTG2 expression through induction of BTG2-targeting miRNAs, not through direct chromatin repression of BTG2; this indirect miRNA-dependent mechanism regulates cell cycle progression in vitro and tumorigenesis in mouse xenograft models.\",\n      \"method\": \"shRNA screen of 43 histone KMTs, miRNA profiling, cell cycle assays, xenograft tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional screen with mechanistic follow-up (miRNA pathway placement), xenograft validation, single lab\",\n      \"pmids\": [\"26394836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Biochemical reconstitution of each human SET1 family core complex shows that in the absence of WRAD all SET domains catalyze at least weak H3K4 monomethylation; in the presence of WRAD, all SET1 family members show stimulated monomethyltransferase activity but differ in di- and trimethylation activities correlated with evolutionary lineage; phylogenetic scanning mutagenesis identified a cluster of residues that confer WRAD-dependent gain-of-function dimethylation activity.\",\n      \"method\": \"Biochemical reconstitution of core complexes, in vitro methyltransferase assays, phylogenetic mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic biochemical reconstitution of all SET1 family complexes including SETd1A with mutagenesis\",\n      \"pmids\": [\"25561738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SET1 (SETD1A) mediates H3K4me3 accumulation at the endothelin-1 (EDN1) promoter in endothelial cells upon angiotensin II stimulation; SET1 is recruited to the EDN1 promoter by AP-1 (c-Jun/c-Fos) and synergizes with AP-1 to activate transcription; endothelial-specific deletion of SET1 in mice attenuates Ang II-induced cardiac hypertrophy and fibrosis.\",\n      \"method\": \"ChIP, Co-IP, siRNA knockdown, conditional knockout mice, cardiomyocyte hypertrophy assay\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + Co-IP + in vivo KO with physiological phenotype, single lab\",\n      \"pmids\": [\"25814673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mutation of the Win motif-WDR5 interface severely disrupts assembly and activity of MLL1 and SETd1A complexes but only modestly disrupts MLL2/4 and SETd1B complexes; a peptidomimetic targeting the Win motif-WDR5 interaction selectively inhibits MLL1 and SETd1A core complex activity within the SET1 family.\",\n      \"method\": \"Biochemical reconstitution, in vitro methyltransferase assay, Win motif mutagenesis, peptide inhibitor design and enzymatic assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic reconstitution with mutagenesis and selective inhibitor, multiple SET1 family members compared\",\n      \"pmids\": [\"27563068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Among SET1/MLL family H3K4 methyltransferases, Set1a specifically interacts with Oct4; this interaction is independent of Wdr5; Set1a is recruited to and required for H3K4 methylation at Oct4 target gene promoters; Set1a is required for ES cell maintenance, iPSC generation, and generation of Oct4-positive inner cell mass.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, ChIP-seq, gene knockout, gene expression profiling\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP defining specific Oct4-Set1a interaction, ChIP-seq for genome-wide binding, KO with developmental phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"26785054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The vertebrate SET1 complex is targeted to actively transcribed gene promoters through CFP1, which engages in multivalent chromatin reading involving recognition of non-methylated CpG DNA and H3K4me3; CFP1 defines SET1 complex occupancy on chromatin and its multivalent interactions are required for the SET1 complex to place H3K4me3; loss of CFP1 perturbs gene expression.\",\n      \"method\": \"Live-cell imaging, functional genomics (ChIP-seq), CFP1 point mutant analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging plus genome-wide ChIP-seq plus domain mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"28877467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nup98 binds predominantly to transcription start sites in hematopoietic cells and recruits the Wdr82-Set1A/COMPASS complex, which is required for H3K4me3 deposition; depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and abrogates H3K4me3 at adjacent promoters; AML-associated Nup98 fusion protein causes mislocalization of H3K4me3.\",\n      \"method\": \"ChIP-seq, siRNA knockdown, co-immunoprecipitation, protein localization\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq + RNAi + Co-IP establishing mechanistic pathway of Nup98→Wdr82→Set1A→H3K4me3\",\n      \"pmids\": [\"29269482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Set1 complex directly binds RNA in vitro through the double RRM and N-SET domain of Set1 and through its subunit Spp1; RNA binding (CRAC assay) shows Set1 binds nascent transcripts near transcription start sites; RNA binding is important for appropriate topology of Set1C distribution along transcription units and correlates with efficient H3K4me3 deposition; Set1 also binds non-nascent RNAs including Ty1 retrotransposons and its own mRNA.\",\n      \"method\": \"In vitro RNA binding assay, UV RNA crosslinking (CRAC), ChIP-seq, parallel analysis of RNAPII binding\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus in vivo CRAC crosslinking, single lab\",\n      \"pmids\": [\"29071121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SET1A mediates mono-methylation of YAP at K342, which disrupts YAP's binding to CRM1 and blocks its nuclear export, thereby sequestering active YAP in the nucleus; YAP K342 methylation knockin mice are more susceptible to colorectal tumorigenesis.\",\n      \"method\": \"In vitro methylation assay, co-immunoprecipitation, nuclear export assay, knockin mouse model, mutagenesis\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro methylation of non-histone substrate (YAP K342) plus co-IP for CRM1 interaction plus in vivo knockin mouse, multiple orthogonal methods\",\n      \"pmids\": [\"30008322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SETD1A has an essential non-catalytic function through a newly identified 'FLOS' domain that acts as a cyclin-K-binding site; FLOS disruption suppresses DNA damage response genes and induces p53-dependent apoptosis in AML cells; the FLOS domain is required for chromosomal recruitment of cyclin K and DNA-repair-associated gene expression in S phase; the enzymatic SET domain is not necessary for AML cell survival.\",\n      \"method\": \"CRISPR-Cas9 domain screening, mutagenesis studies, co-immunoprecipitation (SETD1A-cyclin K), ChIP, apoptosis assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR domain screen + mutagenesis + Co-IP + ChIP, published in Cell, identifies non-catalytic function with defined binding partner\",\n      \"pmids\": [\"29474905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SETD1A catalyzes H3K4 methylation at stalled replication forks, which enhances FANCD2-dependent histone chaperone activity; depletion of SETD1A leads to DNA2-dependent resection of damaged replication forks; suppressing H3K4 methylation or expression of a chaperone-defective FANCD2 mutant leads to loss of RAD51 nucleofilament stability and nucleolytic fork degradation.\",\n      \"method\": \"Depletion/siRNA of SETD1A, fork degradation assays, H3K4 methylation ChIP at replication forks, FANCD2 chaperone mutant analysis, RAD51 foci\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — depletion with specific molecular phenotype, epistasis with FANCD2 chaperone mutant, multiple readouts linking SETD1A H3K4me to fork protection\",\n      \"pmids\": [\"29937342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Uhrf1 forms a complex with Setd1a/COMPASS to maintain bivalent H3K4me3/H3K27me3 histone marks in ES cells, particularly those associated with neuroectoderm and mesoderm specification.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, knockdown of Uhrf1\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying complex plus ChIP-seq for genome-wide histone marks, single lab\",\n      \"pmids\": [\"29968706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SETD1A is recruited to the THBD (thrombomodulin) promoter by the transcription factor KLF4 in response to retinoic acid; SETD1A also mediates H3K4me3-dependent upregulation of KLF4 expression via retinoic acid receptor; SETD1A knockdown reduces H3K4me3 at the THBD promoter and blocks retinoic acid-induced thrombomodulin transcription.\",\n      \"method\": \"ChIP, Co-IP, siRNA knockdown, reporter assay\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + Co-IP + KD with functional readout, single lab\",\n      \"pmids\": [\"29940355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SETD1A protects hematopoietic stem cells (HSCs) from activation-induced functional decline; conditional deletion of Setd1a in adult LT-HSCs is compatible with steady-state hematopoiesis but causes loss of transcriptional cellular identity, proliferative capacity, and stem cell function under replicative stress or after transplantation; SETD1A regulates expression of DNA damage recognition and repair pathways in HSCs.\",\n      \"method\": \"Conditional gene knockout (Setd1a-cKO in LT-HSCs), transplantation assays, RNA-seq, ChIP\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with defined functional phenotypes (transplantation, replicative stress), transcriptome analysis, single lab\",\n      \"pmids\": [\"29348130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Setd1a heterozygous loss-of-function mice exhibit axonal branching defects, altered cortical synaptic dynamics, and working memory deficits; Setd1a binds both promoters and enhancers with striking overlap with Mef2 on enhancers; LSD1 is identified as a major counteracting demethylase for Setd1a; pharmacological inhibition of LSD1 rescues behavioral and morphological deficits in Setd1a-deficient mice.\",\n      \"method\": \"Heterozygous mouse model (Setd1a+/-), ChIP-seq for Setd1a binding, morphological analysis of axons, behavioral testing, LSD1 inhibitor treatment\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq + in vivo mouse model with morphological and behavioral phenotypes + pharmacological rescue identifying LSD1 as counteracting demethylase, multiple orthogonal methods\",\n      \"pmids\": [\"31606247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The Set1 N-terminal region and COMPASS subunit Swd2 interact with each other and are both needed for efficient Pol II CTD binding; a single point mutation in Swd2 that affects its interaction with Set1 impairs COMPASS recruitment to chromatin and H3K4 methylation; H2B ubiquitylation is still required for efficient H3K4 methylation even when Set1/COMPASS is recruited via an alternative CTD interaction domain (Nrd1 CID), indicating H2Bub acts after initial COMPASS recruitment.\",\n      \"method\": \"Co-immunoprecipitation, CTD pulldown assays, point mutagenesis of Swd2, ChIP, domain swap experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IP experiments + domain mutagenesis + ChIP establishing the Set1 N-terminal/Swd2 dual CTD-binding mechanism, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"32358498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SETD1A interacts with HIF1α and co-occupies the promoters of glycolytic genes (HK2, PFK2); SETD1A methylates H3K4 at these promoters to strengthen HIF1α transactivation; knockdown of SETD1A reduces H3K4 methylation at HK2 and PFK2 promoters, reduces HIF1α recruitment, and decreases glycolytic gene expression and glycolysis.\",\n      \"method\": \"Co-immunoprecipitation (SETD1A-HIF1α), ChIP (SETD1A and H3K4me3), siRNA knockdown, metabolic assays\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + ChIP + functional KD, single lab\",\n      \"pmids\": [\"32291851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Setd1a haploinsufficiency in mice causes highly variable transcriptional adaptations across different cell types in prefrontal cortex and striatum; Foxp2+ neurons show the most prominent gene expression changes that correlate with changes in H3K4me3; dysregulated genes involve neuron morphogenesis and synaptic function.\",\n      \"method\": \"Single-cell RNA sequencing in Setd1a+/- mice, H3K4me3 ChIP-seq, behavioral assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq + ChIP-seq in mouse model, single lab\",\n      \"pmids\": [\"35245111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Setd1a knockdown in layer 2/3 pyramidal neurons of the medial prefrontal cortex specifically recapitulates impaired sociality; postsynaptic Setd1a is essential for excitatory synaptic transmission as demonstrated by optogenetics-assisted selective stimulation of presynaptic neurons combined with Setd1a RNAi knockdown.\",\n      \"method\": \"Conditional Setd1a knockdown by RNAi in specific neurons, optogenetics, electrophysiology, behavioral assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KD with optogenetics-assisted electrophysiology, single lab\",\n      \"pmids\": [\"32937141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SETD1A interacts with and stabilizes β-catenin (through a SET-domain-independent mechanism) to positively regulate the Wnt/β-catenin pathway; SETD1A also binds to the promoters of NEAT1 and EZH2 to activate transcription via H3K4me3 enrichment, contributing to cancer stem cell properties; a positive feedback loop exists where SETD1A is a direct target of the Wnt/β-catenin pathway.\",\n      \"method\": \"Co-immunoprecipitation (SETD1A-β-catenin), ChIP, luciferase reporter, SET domain deletion mutant analysis\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP + ChIP + reporter assays, single lab, SET domain deletion is partial mechanistic follow-up\",\n      \"pmids\": [\"34645486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"H3K4 methylation by SETD1A-BOD1L facilitates recruitment of RIF1 to DSBs; RIF1 directly binds methylated H3K4; compromising SETD1A or BOD1L expression impairs RIF1 localization to DSBs, leads to uncontrolled DNA end resection, impairs telomere end-joining and class switch recombination; patient cells with SETD1A loss-of-function mutations show RIF1 localization defects; loss of SETD1A-dependent RIF1 recruitment in BRCA1-deficient cells restores homologous recombination.\",\n      \"method\": \"Co-immunoprecipitation, RIF1 foci assays, DNA end-joining assays (telomere FISH, class switch recombination), patient cell lines with SETD1A LoF, BRCA1-deficient cell epistasis, direct binding assay (RIF1 to H3K4me peptides)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct RIF1-H3K4me binding assay + functional epistasis in multiple cell systems including patient cells + multiple DNA repair readouts, single lab but comprehensive\",\n      \"pmids\": [\"35439434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SETD1A haploinsufficiency in human iPSC-derived excitatory/inhibitory neuronal networks results in increased dendritic complexity and increased network bursting activity; perturbations in glutamatergic synaptic function genes and hyperactive cAMP/PKA pathway were identified; pharmacological targeting of the cAMP pathway rescues the network deficits.\",\n      \"method\": \"CRISPR-Cas9 SETD1A+/- iPSC-derived neurons, multi-electrode array, transcriptomics, cAMP pathway pharmacological rescue\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human iPSC model with electrophysiology + transcriptomics + pharmacological rescue identifying cAMP/PKA as downstream pathway, single lab\",\n      \"pmids\": [\"35508131\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SETD1A is the catalytic subunit of a conserved multi-protein COMPASS complex (containing WDR5, RbBP5, ASH2L, DPY30, Wdr82, CFP1, and HCF-1 among others) that primarily trimethylates histone H3 at lysine 4 (H3K4me3) at transcription start sites through co-transcriptional recruitment via Wdr82 binding to the Ser5-phosphorylated Pol II CTD; its methyltransferase activity is stimulated by H2B ubiquitylation (which promotes processivity from mono- to trimethylation) and regulated by an n-SET domain crosstalk mechanism; beyond H3K4, SETD1A monomethylates the non-histone substrate YAP at K342 to block its nuclear export, and its non-catalytic FLOS domain recruits cyclin K to regulate DNA damage response gene expression; SETD1A-dependent H3K4 methylation at replication forks protects nascent DNA from resection via FANCD2 chaperone activity and recruits RIF1 to DSBs to promote NHEJ; in neurons, SETD1A haploinsufficiency disrupts excitatory synaptic function and axonal branching, with LSD1 acting as the primary counteracting demethylase whose inhibition rescues behavioral deficits.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SETD1A is the catalytic subunit of a conserved multi-protein COMPASS/Set1 complex that deposits histone H3 lysine 4 methylation, the dominant H3K4 methyltransferase activity in eukaryotic cells [#0, #4]. Within the complex, the WRAD module (WDR5, RbBP5, ASH2L, DPY30) and the Win-motif/WDR5 interface are required for assembly and for stimulating SETD1A's progression from mono- to di- and trimethylation, while a Phe/Tyr switch and the n-SET domain govern trimethyltransferase output and read H2B ubiquitylation crosstalk that controls processivity [#16, #23, #25, #18, #5]. The complex is targeted to active promoters and transcription start sites co-transcriptionally: Wdr82 and the Set1 N-terminal/Swd2 module bind the Ser5-phosphorylated Pol II CTD, CFP1 reads non-methylated CpG DNA and H3K4me3, and recruitment is further directed by Nup98, TET/OGT-modified HCF-1, and sequence-specific factors including p53, Oct4, KLF4, HIF1\\u03b1, and AP-1 [#10, #37, #27, #28, #17, #19, #26]. Beyond chromatin, SETD1A monomethylates the non-histone substrate YAP at K342 to block CRM1-dependent nuclear export and, through its non-catalytic FLOS domain, recruits cyclin K to drive DNA-damage-response gene expression independently of its SET domain [#30, #31]. At the genome, SETD1A-dependent H3K4 methylation protects stalled replication forks via FANCD2 chaperone activity and recruits RIF1 to double-strand breaks to bias repair toward end-joining [#32, #42]. SETD1A is essential for embryonic development, pluripotency, and hematopoietic stem cell maintenance, and its haploinsufficiency disrupts excitatory synaptic function, dendritic and axonal morphology, and behavior, with the demethylase LSD1 acting as a counteracting eraser whose inhibition rescues these deficits [#21, #35, #36, #43].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that Set1/SETD1A is itself an enzyme and the principal cellular source of H3K4 methylation, and that it acts within a defined multi-subunit complex rather than alone.\",\n      \"evidence\": \"Genetic deletion with complementation rescue in yeast and Co-IP/MS identification of the eight-subunit Set1C/COMPASS\",\n      \"pmids\": [\"11751634\", \"11742990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define how the complex is targeted to specific genes\", \"Subunit functions within the complex not yet assigned\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved how the complex is delivered to active genes by linking Set1 recruitment to the transcribing polymerase, defining co-transcriptional deposition of H3K4me.\",\n      \"evidence\": \"ChIP, Co-IP and genetic epistasis showing Set1 binds the Ser5-phosphorylated Pol II CTD and depends on Paf1/CTD kinase; human Set1/Ash2 shown to methylate H3K4 and to be tethered with HCF-1\",\n      \"pmids\": [\"12667453\", \"12670868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CTD-binding subunit not yet identified\", \"Does not explain control of methylation degree\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the determinants of methylation degree and substrate breadth, showing H2B ubiquitylation, the Set1 N-terminus, and an RRM control mono-versus-trimethylation, and that Set1 can methylate a non-histone kinetochore substrate.\",\n      \"evidence\": \"Genetic H2B-K123 mutation, N-terminal mutagenesis, RRM1 crystal structure/RNA binding, CFP1 identification, and in vitro methylation of Dam1 with ipl1-2 suppressor analysis\",\n      \"pmids\": [\"16039595\", \"15964832\", \"15775977\", \"16253997\", \"16143104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling H2Bub to processivity not yet structural\", \"Generality of non-histone methylation to mammalian SETD1A untested at this stage\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified Wdr82 as the CTD-binding adaptor specific to Set1A/B complexes, mechanistically explaining how SETD1A (not MLL complexes) is positioned at transcription start sites.\",\n      \"evidence\": \"Co-IP, peptide binding to Ser5-phospho CTD, ChIP and siRNA knockdown; AP-MS confirming Wdr82 as Set1-specific\",\n      \"pmids\": [\"17998332\", \"18838538\", \"17578910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address DNA-sequence-level targeting\", \"Relative contribution of Wdr82 versus other adaptors unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Dissected complex architecture and catalytic chemistry, assigning subunit roles in stability and trimethylation and placing H3K4me2 upstream of deacetylase recruitment and elongation.\",\n      \"evidence\": \"Subunit deletion/Co-IP, structure-guided Tyr1052 mutagenesis, and PHD-finger binding linking H3K4me2 to Set3C recruitment\",\n      \"pmids\": [\"16921172\", \"19398585\", \"19379692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic-state transitions not captured structurally\", \"Downstream readers of H3K4me3 in this context not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the WDR5-Win motif interface as the assembly hub that licenses SETD1A catalytic stimulation by RbBP5-ASH2L.\",\n      \"evidence\": \"Crystal structures of WDR5-Win complexes plus in vitro methyltransferase assays\",\n      \"pmids\": [\"22266653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish in-cell dependence of SETD1A on this interface\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected SETD1A targeting to upstream signaling and chromatin context, showing p53/p300 acetylation, TET/OGT-modified HCF-1, and the n-SET/H2Bub crosstalk module direct and license its activity.\",\n      \"evidence\": \"In vitro reconstitution on recombinant chromatin, Co-IP, ChIP, MS-PTM identification of HCF1 GlcNAcylation, and n-SET domain reconstitution extended to the human complex\",\n      \"pmids\": [\"23870121\", \"23353889\", \"23453808\", \"23508102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative hierarchy among these recruitment cues unknown\", \"How signaling switches between targets not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established SETD1A as developmentally essential and non-redundant with SETD1B, tying its H3K4 methyltransferase activity to pluripotency and proliferation.\",\n      \"evidence\": \"Conditional mouse knockout, ES cell deletion with H3K4me loss and G1 arrest, and failed Setd1b rescue\",\n      \"pmids\": [\"24550110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of SETD1A/SETD1B non-redundancy not defined\", \"Direct target genes driving proliferation arrest not enumerated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Refined targeting and selectivity, showing CFP1 multivalent chromatin reading and Oct4-specific recruitment define SETD1A occupancy, and that the Win-WDR5 interface is selectively required for SETD1A among the family.\",\n      \"evidence\": \"Live imaging, ChIP-seq, CFP1 point mutants, Oct4 Co-IP/ChIP-seq, and Win-motif peptidomimetic inhibition\",\n      \"pmids\": [\"28877467\", \"26785054\", \"27563068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between CFP1 reading and transcription-factor recruitment unresolved\", \"Selective inhibitor effects on non-catalytic functions untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Uncovered catalytic and non-catalytic functions beyond promoter H3K4me3: monomethylation of YAP to control its localization, a FLOS domain that recruits cyclin K, and roles protecting replication forks via FANCD2.\",\n      \"evidence\": \"In vitro methylation and nuclear export assays with YAP knockin mice; CRISPR domain screen, mutagenesis and SETD1A-cyclin K Co-IP; fork degradation and FANCD2 chaperone-mutant analysis\",\n      \"pmids\": [\"30008322\", \"29474905\", \"29937342\", \"29968706\", \"29940355\", \"29348130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full non-histone substrate repertoire unknown\", \"Separation of catalytic versus FLOS-domain contributions in normal tissues unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the neuronal consequences of SETD1A haploinsufficiency and identified LSD1 as the counteracting demethylase, providing a pharmacologically tractable axis.\",\n      \"evidence\": \"Setd1a+/- mice with ChIP-seq, axonal/synaptic morphology, behavior, and LSD1 inhibitor rescue\",\n      \"pmids\": [\"31606247\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal target genes mediating behavioral phenotypes not pinpointed\", \"Cell-type specificity of LSD1 antagonism not fully mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mechanistically extended recruitment and CTD-engagement models and dissected cell-type-specific transcriptional and synaptic effects of haploinsufficiency.\",\n      \"evidence\": \"Swd2/Set1 N-terminal CTD-binding mutagenesis with ChIP; scRNA-seq and H3K4me3 ChIP-seq in Setd1a+/- mice; cell-type-specific RNAi with optogenetics-electrophysiology; HIF1\\u03b1 Co-IP/ChIP at glycolytic promoters\",\n      \"pmids\": [\"32358498\", \"35245111\", \"32937141\", \"32291851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single mark produces variable cell-type adaptations unresolved\", \"Direct link from glycolytic-gene regulation to organismal phenotypes untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a direct H3K4-methyl reader axis in DNA repair and a translatable downstream pathway in neurons, showing RIF1 binds SETD1A/BOD1L-deposited H3K4me to bias end-joining, and that cAMP/PKA hyperactivity underlies network deficits in patient-derived neurons.\",\n      \"evidence\": \"Direct RIF1-H3K4me peptide binding, end-joining and BRCA1 epistasis assays in patient cells; SETD1A+/- iPSC neurons with multi-electrode arrays, transcriptomics, and cAMP pathway rescue\",\n      \"pmids\": [\"35439434\", \"35508131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same axis operates at endogenous DSBs genome-wide unsettled\", \"Link between repair function and neuropsychiatric phenotype not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SETD1A's distinct activities — promoter H3K4me3, non-histone methylation, FLOS-mediated cyclin K recruitment, fork protection, and DSB repair — are partitioned and prioritized within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model integrating catalytic and non-catalytic functions\", \"Determinants selecting among competing targets unknown\", \"Substrate specificity rules for non-histone methylation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3, 4, 23, 30]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [7, 30]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [18, 27]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [8, 29]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [19, 26, 38]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 15]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3, 19, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 10, 19, 27]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [4, 18, 27, 33]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [31, 32, 42]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [21, 26, 36]}\n    ],\n    \"complexes\": [\"COMPASS/Set1 complex\", \"kinetochore (Dam1 substrate)\"],\n    \"partners\": [\"WDR5\", \"CFP1/CXXC1\", \"Wdr82\", \"HCF-1\", \"RbBP5\", \"ASH2L\", \"RIF1\", \"cyclin K\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}