Affinage

SETD1A

Histone-lysine N-methyltransferase SETD1A · UniProt O15047

Length
1707 aa
Mass
186.0 kDa
Annotated
2026-06-10
100 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2001 High

    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

    PMID:11742990 PMID:11751634

    Open questions at the time
    • Does not define how the complex is targeted to specific genes
    • Subunit functions within the complex not yet assigned
  2. 2003 High

    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

    PMID:12667453 PMID:12670868

    Open questions at the time
    • Direct CTD-binding subunit not yet identified
    • Does not explain control of methylation degree
  3. 2005 High

    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

    PMID:15775977 PMID:15964832 PMID:16039595 PMID:16143104 PMID:16253997

    Open questions at the time
    • Mechanism coupling H2Bub to processivity not yet structural
    • Generality of non-histone methylation to mammalian SETD1A untested at this stage
  4. 2007 High

    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

    PMID:17578910 PMID:17998332 PMID:18838538

    Open questions at the time
    • Does not address DNA-sequence-level targeting
    • Relative contribution of Wdr82 versus other adaptors unresolved
  5. 2009 High

    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

    PMID:16921172 PMID:19379692 PMID:19398585

    Open questions at the time
    • Catalytic-state transitions not captured structurally
    • Downstream readers of H3K4me3 in this context not defined
  6. 2012 High

    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

    PMID:22266653

    Open questions at the time
    • Does not establish in-cell dependence of SETD1A on this interface
  7. 2013 High

    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

    PMID:23353889 PMID:23453808 PMID:23508102 PMID:23870121

    Open questions at the time
    • Quantitative hierarchy among these recruitment cues unknown
    • How signaling switches between targets not resolved
  8. 2014 High

    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

    PMID:24550110

    Open questions at the time
    • Molecular basis of SETD1A/SETD1B non-redundancy not defined
    • Direct target genes driving proliferation arrest not enumerated
  9. 2016 High

    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

    PMID:26785054 PMID:27563068 PMID:28877467

    Open questions at the time
    • Interplay between CFP1 reading and transcription-factor recruitment unresolved
    • Selective inhibitor effects on non-catalytic functions untested
  10. 2018 High

    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

    PMID:29348130 PMID:29474905 PMID:29937342 PMID:29940355 PMID:29968706 PMID:30008322

    Open questions at the time
    • Full non-histone substrate repertoire unknown
    • Separation of catalytic versus FLOS-domain contributions in normal tissues unclear
  11. 2019 High

    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

    PMID:31606247

    Open questions at the time
    • Causal target genes mediating behavioral phenotypes not pinpointed
    • Cell-type specificity of LSD1 antagonism not fully mapped
  12. 2020 High

    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

    PMID:32291851 PMID:32358498 PMID:32937141 PMID:35245111

    Open questions at the time
    • How a single mark produces variable cell-type adaptations unresolved
    • Direct link from glycolytic-gene regulation to organismal phenotypes untested
  13. 2022 High

    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

    PMID:35439434 PMID:35508131

    Open questions at the time
    • Whether the same axis operates at endogenous DSBs genome-wide unsettled
    • Link between repair function and neuropsychiatric phenotype not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0140110 transcription regulator activity 3 GO:0003723 RNA binding 2 GO:0042393 histone binding 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2
Pathway
R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-73894 DNA Repair 3
Partners
ASH2LCFP1/CXXC1CYCLIN KHCF-1RBBP5RIF1WDR5WDR82
Complex memberships
COMPASS/Set1 complexkinetochore (Dam1 substrate)

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 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. Genetic deletion, in vivo histone methylation assay with methyl-specific antiserum, complementation rescue Genes & development High 11742990 11751634
2001 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. Co-immunoprecipitation, mass spectrometry, biochemical fractionation The EMBO journal High 11742990
2003 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. Chromatin immunoprecipitation (ChIP), co-immunoprecipitation, genetic epistasis with CTD kinase and Paf1 complex mutants Molecular cell High 12667453
2003 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. In vitro histone methyltransferase assay, co-immunoprecipitation, domain mapping Genes & development High 12670868
2005 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. Co-immunoprecipitation, mass spectrometry, in vitro methyltransferase assay, confocal microscopy, genetic knockout of CFP1 The Journal of biological chemistry High 16253997
2005 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. Chromatin immunoprecipitation, mass spectrometry, genetic mutation of H2B K123 Molecular cell High 16039595
2005 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. Yeast genetics, site-directed mutagenesis, chromatin immunoprecipitation, silencing assays The Journal of biological chemistry Medium 15964832
2005 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. Genetic epistasis (suppressor analysis of ipl1-2), biochemical methylation assay of Dam1, genetic double-mutant analysis Cell High 16143104
2005 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. Crystal structure of RRM1, RNA-binding assay in vitro, in vivo H3K4 methylation analysis by ChIP, site-directed mutagenesis The EMBO journal High 15775977
2006 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. Co-immunoprecipitation, genetic deletion of individual subunits, western blot for Set1 levels, ChIP The Journal of biological chemistry High 16921172
2007 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. Co-immunoprecipitation, peptide binding assays, chromatin immunoprecipitation, siRNA knockdown Molecular and cellular biology High 17998332
2007 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. ChIP at viral promoters, epistasis with HCF-1, promoter reporter assays Proceedings of the National Academy of Sciences of the United States of America Medium 17578910
2008 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. Affinity purification/mass spectrometry, RNAi knockdown, in vitro histone methyltransferase assay Molecular and cellular biology High 18838538
2009 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. Homology modeling, site-directed mutagenesis, in vivo H3K4 methylation analysis, ChIP Molecular and cellular biology Medium 19398585
2009 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. Genetic epistasis, ChIP, PHD finger binding assay, growth assays on mycophenolic acid Cell High 19379692
2009 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. Confocal microscopy, genetic knockout (CXXC1-/-), structure-function analysis of CFP1 point mutations and truncations The FEBS journal Medium 19951360
2012 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. Crystal structure determination, biochemical binding assays, in vitro methyltransferase assay Nucleic acids research High 22266653
2013 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. Co-immunoprecipitation, ChIP, OGT activity assays, knockdown of TET2/3 and OGT, mass spectrometry identification of HCF1 GlcNAcylation The EMBO journal High 23353889
2013 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. In vitro histone methyltransferase assay with reconstituted yeast Set1 complex and fully ubiquitylated H2B chromatin template, n-SET domain mutagenesis, genetic analyses Molecular cell High 23453808
2013 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. In vitro transcription/methylation assay with recombinant chromatin, Co-IP, ChIP, cell-based assays with DNA damage Cell High 23870121
2013 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. Label-free quantitative mass spectrometry, affinity purification Molecular and cellular biology Medium 23508102
2014 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. Conditional gene knockout in mice, ES cell deletion, western blot for H3K4 methylation, flow cytometry for cell cycle Development High 24550110
2015 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. shRNA screen of 43 histone KMTs, miRNA profiling, cell cycle assays, xenograft tumor models Nature communications Medium 26394836
2015 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. Biochemical reconstitution of core complexes, in vitro methyltransferase assays, phylogenetic mutagenesis The Journal of biological chemistry High 25561738
2015 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. ChIP, Co-IP, siRNA knockdown, conditional knockout mice, cardiomyocyte hypertrophy assay Arteriosclerosis, thrombosis, and vascular biology Medium 25814673
2016 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. Biochemical reconstitution, in vitro methyltransferase assay, Win motif mutagenesis, peptide inhibitor design and enzymatic assay The Journal of biological chemistry High 27563068
2016 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. Co-immunoprecipitation, ChIP, ChIP-seq, gene knockout, gene expression profiling Stem cells High 26785054
2017 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. Live-cell imaging, functional genomics (ChIP-seq), CFP1 point mutant analysis Cell reports High 28877467
2017 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. ChIP-seq, siRNA knockdown, co-immunoprecipitation, protein localization Genes & development High 29269482
2017 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. In vitro RNA binding assay, UV RNA crosslinking (CRAC), ChIP-seq, parallel analysis of RNAPII binding Cell discovery Medium 29071121
2018 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. In vitro methylation assay, co-immunoprecipitation, nuclear export assay, knockin mouse model, mutagenesis Cancer cell High 30008322
2018 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. CRISPR-Cas9 domain screening, mutagenesis studies, co-immunoprecipitation (SETD1A-cyclin K), ChIP, apoptosis assays Cell High 29474905
2018 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. Depletion/siRNA of SETD1A, fork degradation assays, H3K4 methylation ChIP at replication forks, FANCD2 chaperone mutant analysis, RAD51 foci Molecular cell High 29937342
2018 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. Co-immunoprecipitation, ChIP-seq, knockdown of Uhrf1 Nature communications Medium 29968706
2018 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. ChIP, Co-IP, siRNA knockdown, reporter assay Biochimica et biophysica acta. Gene regulatory mechanisms Medium 29940355
2018 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. Conditional gene knockout (Setd1a-cKO in LT-HSCs), transplantation assays, RNA-seq, ChIP Blood High 29348130
2019 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. Heterozygous mouse model (Setd1a+/-), ChIP-seq for Setd1a binding, morphological analysis of axons, behavioral testing, LSD1 inhibitor treatment Neuron High 31606247
2020 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. Co-immunoprecipitation, CTD pulldown assays, point mutagenesis of Swd2, ChIP, domain swap experiments Nature communications High 32358498
2020 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. Co-immunoprecipitation (SETD1A-HIF1α), ChIP (SETD1A and H3K4me3), siRNA knockdown, metabolic assays Molecular oncology Medium 32291851
2020 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. Single-cell RNA sequencing in Setd1a+/- mice, H3K4me3 ChIP-seq, behavioral assays Science advances Medium 35245111
2020 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. Conditional Setd1a knockdown by RNAi in specific neurons, optogenetics, electrophysiology, behavioral assays Cell reports Medium 32937141
2021 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. Co-immunoprecipitation (SETD1A-β-catenin), ChIP, luciferase reporter, SET domain deletion mutant analysis Journal of experimental & clinical cancer research Medium 34645486
2022 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. 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) Molecular cell High 35439434
2022 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. CRISPR-Cas9 SETD1A+/- iPSC-derived neurons, multi-electrode array, transcriptomics, cAMP pathway pharmacological rescue Cell reports Medium 35508131

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity. Molecular cell 892 12667453
2001 The Saccharomyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone 3 lysine 4. The EMBO journal 503 11742990
2001 Histone H3 lysine 4 methylation is mediated by Set1 and required for cell growth and rDNA silencing in Saccharomyces cerevisiae. Genes & development 500 11751634
2013 TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. The EMBO journal 411 23353889
2016 Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. Nature neuroscience 338 26974950
2003 Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1. Genes & development 337 12670868
2009 Dimethylation of H3K4 by Set1 recruits the Set3 histone deacetylase complex to 5' transcribed regions. Cell 267 19379692
2008 Molecular regulation of H3K4 trimethylation by Wdr82, a component of human Set1/COMPASS. Molecular and cellular biology 258 18838538
2005 CpG-binding protein (CXXC finger protein 1) is a component of the mammalian Set1 histone H3-Lys4 methyltransferase complex, the analogue of the yeast Set1/COMPASS complex. The Journal of biological chemistry 258 16253997
1997 SET1, a yeast member of the trithorax family, functions in transcriptional silencing and diverse cellular processes. Molecular biology of the cell 216 9398665
2005 Histone H2B ubiquitylation controls processive methylation but not monomethylation by Dot1 and Set1. Molecular cell 201 16039595
2013 Quantitative dissection and stoichiometry determination of the human SET1/MLL histone methyltransferase complexes. Molecular and cellular biology 181 23508102
2007 Wdr82 is a C-terminal domain-binding protein that recruits the Setd1A Histone H3-Lys4 methyltransferase complex to transcription start sites of transcribed human genes. Molecular and cellular biology 176 17998332
2002 Evidence that Set1, a factor required for methylation of histone H3, regulates rDNA silencing in S. cerevisiae by a Sir2-independent mechanism. Current biology : CB 176 11818070
2012 Spp1, a member of the Set1 Complex, promotes meiotic DSB formation in promoters by tethering histone H3K4 methylation sites to chromosome axes. Molecular cell 159 23246437
2014 The H3K4 methyltransferase Setd1a is first required at the epiblast stage, whereas Setd1b becomes essential after gastrulation. Development (Cambridge, England) 153 24550110
2011 Drosophila Set1 is the major histone H3 lysine 4 trimethyltransferase with role in transcription. The EMBO journal 153 21694722
2014 Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene. Neuron 149 24853937
2018 SET1A-Mediated Mono-Methylation at K342 Regulates YAP Activation by Blocking Its Nuclear Export and Promotes Tumorigenesis. Cancer cell 148 30008322
2013 SET1 and p300 act synergistically, through coupled histone modifications, in transcriptional activation by p53. Cell 142 23870121
2006 Protein interactions within the Set1 complex and their roles in the regulation of histone 3 lysine 4 methylation. The Journal of biological chemistry 129 16921172
2005 The Set1 methyltransferase opposes Ipl1 aurora kinase functions in chromosome segregation. Cell 125 16143104
2013 The n-SET domain of Set1 regulates H2B ubiquitylation-dependent H3K4 methylation. Molecular cell 114 23453808
2016 Set1/COMPASS and Mediator are repurposed to promote epigenetic transcriptional memory. eLife 112 27336723
2007 The coactivator host cell factor-1 mediates Set1 and MLL1 H3K4 trimethylation at herpesvirus immediate early promoters for initiation of infection. Proceedings of the National Academy of Sciences of the United States of America 112 17578910
2012 WRAD: enabler of the SET1-family of H3K4 methyltransferases. Briefings in functional genomics 108 22652693
2012 The plasticity of WDR5 peptide-binding cleft enables the binding of the SET1 family of histone methyltransferases. Nucleic acids research 104 22266653
2019 Recapitulation and Reversal of Schizophrenia-Related Phenotypes in Setd1a-Deficient Mice. Neuron 98 31606247
2000 Identification of a novel gene cluster encoding staphylococcal exotoxin-like proteins: characterization of the prototypic gene and its protein product, SET1. Infection and immunity 95 10899837
2018 A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response. Cell 94 29474905
2018 Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2. Molecular cell 94 29937342
2015 Biochemical reconstitution and phylogenetic comparison of human SET1 family core complexes involved in histone methylation. The Journal of biological chemistry 92 25561738
2005 Global loss of Set1-mediated H3 Lys4 trimethylation is associated with silencing defects in Saccharomyces cerevisiae. The Journal of biological chemistry 85 15964832
2017 Histone H3K4 methylation-dependent and -independent functions of Set1A/COMPASS in embryonic stem cell self-renewal and differentiation. Genes & development 84 28939616
2011 A role for Set1/MLL-related components in epigenetic regulation of the Caenorhabditis elegans germ line. PLoS genetics 83 21455483
2005 Histone trimethylation by Set1 is coordinated by the RRM, autoinhibitory, and catalytic domains. The EMBO journal 80 15775977
2017 The SET1 Complex Selects Actively Transcribed Target Genes via Multivalent Interaction with CpG Island Chromatin. Cell reports 79 28877467
2017 Nup98 recruits the Wdr82-Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells. Genes & development 73 29269482
2006 The multiple faces of Set1. Biochemistry and cell biology = Biochimie et biologie cellulaire 73 16936826
2007 Antagonistic functions of SET-2/SET1 and HPL/HP1 proteins in C. elegans development. Developmental biology 62 17967446
2020 Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome. Molecular psychiatry 59 32346159
2020 Setd1a Insufficiency in Mice Attenuates Excitatory Synaptic Function and Recapitulates Schizophrenia-Related Behavioral Abnormalities. Cell reports 59 32937141
2016 Targeted Disruption of the Interaction between WD-40 Repeat Protein 5 (WDR5) and Mixed Lineage Leukemia (MLL)/SET1 Family Proteins Specifically Inhibits MLL1 and SETd1A Methyltransferase Complexes. The Journal of biological chemistry 59 27563068
2022 Loss-of-function variants in the schizophrenia risk gene SETD1A alter neuronal network activity in human neurons through the cAMP/PKA pathway. Cell reports 56 35508131
2011 H3K4 trimethylation by Set1 promotes efficient termination by the Nrd1-Nab3-Sen1 pathway. Molecular and cellular biology 56 21709022
2014 The DPY30 subunit in SET1/MLL complexes regulates the proliferation and differentiation of hematopoietic progenitor cells. Blood 54 25139354
2017 Targeting human SET1/MLL family of proteins. Protein science : a publication of the Protein Society 53 28160335
2015 Histone Methyltransferase SET1 Mediates Angiotensin II-Induced Endothelin-1 Transcription and Cardiac Hypertrophy in Mice. Arteriosclerosis, thrombosis, and vascular biology 53 25814673
2016 Counteracting H3K4 methylation modulators Set1 and Jhd2 co-regulate chromatin dynamics and gene transcription. Nature communications 52 27325136
2015 Set1 and MLL1/2 Target Distinct Sets of Functionally Different Genomic Loci In Vivo. Cell reports 52 26711341
2009 CXXC finger protein 1 restricts the Setd1A histone H3K4 methyltransferase complex to euchromatin. The FEBS journal 52 19951360
2020 Histone methyltransferase SETD1A interacts with HIF1α to enhance glycolysis and promote cancer progression in gastric cancer. Molecular oncology 50 32291851
2020 The complex activities of the SET1/MLL complex core subunits in development and disease. Biochimica et biophysica acta. Gene regulatory mechanisms 48 32302696
2014 The SET-2/SET1 histone H3K4 methyltransferase maintains pluripotency in the Caenorhabditis elegans germline. Cell reports 48 25310986
2015 SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes. Nature communications 47 26394836
2009 Regulation of H3K4 trimethylation via Cps40 (Spp1) of COMPASS is monoubiquitination independent: implication for a Phe/Tyr switch by the catalytic domain of Set1. Molecular and cellular biology 47 19398585
2016 H3K4 Methyltransferase Set1a Is A Key Oct4 Coactivator Essential for Generation of Oct4 Positive Inner Cell Mass. Stem cells (Dayton, Ohio) 46 26785054
2006 Structural characterization of Set1 RNA recognition motifs and their role in histone H3 lysine 4 methylation. Journal of molecular biology 46 16787775
2021 An SETD1A/Wnt/β-catenin feedback loop promotes NSCLC development. Journal of experimental & clinical cancer research : CR 45 34645486
2020 The Set1 N-terminal domain and Swd2 interact with RNA polymerase II CTD to recruit COMPASS. Nature communications 45 32358498
2019 Physical and functional interaction between SET1/COMPASS complex component CFP-1 and a Sin3S HDAC complex in C. elegans. Nucleic acids research 42 31602465
2018 Set1 and Kdm5 are antagonists for H3K4 methylation and regulators of the major conidiation-specific transcription factor gene ABA1 in Fusarium fujikuroi. Environmental microbiology 42 30047187
2014 Context dependency of Set1/COMPASS-mediated histone H3 Lys4 trimethylation. Genes & development 42 24402317
2012 Epigenetic regulation of planarian stem cells by the SET1/MLL family of histone methyltransferases. Epigenetics 42 23235145
2018 Uhrf1 regulates active transcriptional marks at bivalent domains in pluripotent stem cells through Setd1a. Nature communications 41 29968706
2016 Setd1a and NURF mediate chromatin dynamics and gene regulation during erythroid lineage commitment and differentiation. Nucleic acids research 41 27141965
2013 Histone H3K27 trimethylation inhibits H3 binding and function of SET1-like H3K4 methyltransferase complexes. Molecular and cellular biology 41 24126056
2012 CENP-B cooperates with Set1 in bidirectional transcriptional silencing and genome organization of retrotransposons. Molecular and cellular biology 41 22907751
2014 Feedback control of Set1 protein levels is important for proper H3K4 methylation patterns. Cell reports 40 24613354
2021 BACH1 recruits NANOG and histone H3 lysine 4 methyltransferase MLL/SET1 complexes to regulate enhancer-promoter activity and maintains pluripotency. Nucleic acids research 39 33503260
2018 The histone methyltransferase SETD1A regulates thrombomodulin transcription in vascular endothelial cells. Biochimica et biophysica acta. Gene regulatory mechanisms 39 29940355
2018 Aberrant expression of SETD1A promotes survival and migration of estrogen receptor α-positive breast cancer cells. International journal of cancer 39 30191958
2016 The enzymes LSD1 and Set1A cooperate with the viral protein HBx to establish an active hepatitis B viral chromatin state. Scientific reports 39 27174370
2015 RETRACTED: SET1A Cooperates With CUDR to Promote Liver Cancer Growth and Hepatocyte-like Stem Cell Malignant Transformation Epigenetically. Molecular therapy : the journal of the American Society of Gene Therapy 39 26581161
2019 De Novo and Inherited SETD1A Variants in Early-onset Epilepsy. Neuroscience bulletin 38 31197650
2020 SET1/MLL family of proteins: functions beyond histone methylation. Epigenetics 35 32795105
2017 Diverse roles of WDR5-RbBP5-ASH2L-DPY30 (WRAD) complex in the functions of the SET1 histone methyltransferase family. Journal of biosciences 35 28229975
2018 SETD1A protects HSCs from activation-induced functional decline in vivo. Blood 34 29348130
2018 The PHD finger protein Spp1 has distinct functions in the Set1 and the meiotic DSB formation complexes. PLoS genetics 34 29444071
2014 Setd1a regulates progenitor B-cell-to-precursor B-cell development through histone H3 lysine 4 trimethylation and Ig heavy-chain rearrangement. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34 25550471
2013 H3K4 methyltransferase Set1 is involved in maintenance of ergosterol homeostasis and resistance to Brefeldin A. Proceedings of the National Academy of Sciences of the United States of America 34 23382196
2006 Developmental timing in Dictyostelium is regulated by the Set1 histone methyltransferase. Developmental biology 34 16469305
2019 Taurine Promotes Milk Synthesis via the GPR87-PI3K-SETD1A Signaling in BMECs. Journal of agricultural and food chemistry 33 30678459
2022 Cell type-specific mechanism of Setd1a heterozygosity in schizophrenia pathogenesis. Science advances 32 35245111
2020 Aberrant Cortical Ensembles and Schizophrenia-like Sensory Phenotypes in Setd1a+/- Mice. Biological psychiatry 32 32143831
2014 Multifaceted genome control by Set1 Dependent and Independent of H3K4 methylation and the Set1C/COMPASS complex. PLoS genetics 32 25356590
2017 The C. elegans SET-2/SET1 histone H3 Lys4 (H3K4) methyltransferase preserves genome stability in the germline. DNA repair 31 28779964
2006 Candida albicans SET1 encodes a histone 3 lysine 4 methyltransferase that contributes to the pathogenesis of invasive candidiasis. Molecular microbiology 31 16629671
2022 H3K4 methylation by SETD1A/BOD1L facilitates RIF1-dependent NHEJ. Molecular cell 29 35439434
2020 SETD1A Promotes Proliferation of Castration-Resistant Prostate Cancer Cells via FOXM1 Transcription. Cancers 29 32629770
2017 Binding to RNA regulates Set1 function. Cell discovery 29 29071121
2017 RNA Binding by Histone Methyltransferases Set1 and Set2. Molecular and cellular biology 28 28483910
2016 Pax6 associates with H3K4-specific histone methyltransferases Mll1, Mll2, and Set1a and regulates H3K4 methylation at promoters and enhancers. Epigenetics & chromatin 27 27617035
2015 Physical Interactions and Functional Coordination between the Core Subunits of Set1/Mll Complexes and the Reprogramming Factors. PloS one 27 26691508
2021 SETD1A Mediated H3K4 Methylation and Its Role in Neurodevelopmental and Neuropsychiatric Disorders. Frontiers in molecular neuroscience 26 34803610
2020 SETD1A augments sorafenib primary resistance via activating YAP in hepatocellular carcinoma. Life sciences 25 32918976
2020 Insights on the regulation of the MLL/SET1 family histone methyltransferases. Biochimica et biophysica acta. Gene regulatory mechanisms 24 32304759
2022 The Set1 Histone H3K4 Methyltransferase Contributes to Azole Susceptibility in a Species-Specific Manner by Differentially Altering the Expression of Drug Efflux Pumps and the Ergosterol Gene Pathway. Antimicrobial agents and chemotherapy 23 35471041
2019 The Set1 complex is dimeric and acts with Jhd2 demethylation to convey symmetrical H3K4 trimethylation. Genes & development 21 30842216
2023 MUC1-C intersects chronic inflammation with epigenetic reprogramming by regulating the set1a compass complex in cancer progression. Communications biology 20 37821650

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