Affinage

ASH2L

Set1/Ash2 histone methyltransferase complex subunit ASH2 · UniProt Q9UBL3

Length
628 aa
Mass
68.7 kDa
Annotated
2026-04-28
77 papers in source corpus 45 papers cited in narrative 45 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ASH2L is an obligatory core subunit of all SET1/MLL-family (COMPASS) histone H3 lysine 4 methyltransferase complexes, serving as a scaffold that couples chromatin recruitment to catalytic activation across eukaryotes. Its N-terminal winged-helix/forkhead-like domain directly binds DNA to target COMPASS to specific genomic loci and senses histone H2B ubiquitylation via residue K99 to stimulate H3K4 mono-, di-, and trimethylation, while its C-terminal SDI domain binds and stabilizes DPY30, which in turn compacts and activates the holoenzyme (PMID:21642971, PMID:23453805, PMID:36065180). Diverse transcription factors—including MYC, NF-Y, GATA3, Mef2d, and OCT4—recruit ASH2L to promoters and super-enhancers, and ASH2L itself is regulated by PRMT1/5-mediated arginine methylation and AARS1/HDAC1-mediated lysine lactylation, integrating signaling inputs into the H3K4 methylation landscape (PMID:24782528, PMID:21445285, PMID:31555818, PMID:21285357, PMID:40726441). Conditional knockouts across tissues demonstrate that ASH2L is essential for embryogenesis, hematopoiesis, neurogenesis, spermatogenesis, and maintenance of chromatin accessibility, and additionally ASH2L can act non-canonically by forming a complex with KLF5 and FBXW7 to promote ubiquitin-proteasomal degradation of KLF5 independently of H3K4 methylation (PMID:31164666, PMID:31315048, PMID:39996311, PMID:36513698).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 Medium

    Establishing that ASH2 resides in a dedicated multiprotein complex distinct from other chromatin remodelers set the stage for identifying its biochemical function.

    Evidence Biochemical fractionation of Drosophila embryo extracts resolved ASH2 in a ~500 kDa complex separate from BRM and ASH1 complexes.

    PMID:9735357

    Open questions at the time
    • Complex composition unknown
    • Enzymatic activity of the ASH2-containing complex not determined
  2. 2001 High

    Discovery that the yeast ASH2 homologue Bre2 is an integral subunit of the Set1 H3K4 methyltransferase complex established ASH2L's biochemical identity as a core COMPASS component.

    Evidence Biochemical purification and mass spectrometry of S. cerevisiae Set1C; in vitro HMT assay showed Bre2 is required for H3K4 methylation.

    PMID:11742990

    Open questions at the time
    • Whether the mammalian homologue ASH2L functions identically was untested
    • Catalytic contribution of Bre2 versus structural role unclear
  3. 2003 High

    Demonstrating that human ASH2L is a core subunit of a Set1-family HMT complex that methylates H3K4 and is tethered by HCF-1 extended the yeast paradigm to mammals and revealed regulatory integration with HDAC complexes.

    Evidence Co-IP, GST pulldown, and in vitro HMT assay in human cells showed ASH2L-containing complex methylates H3K4; H3K9me blocks this activity.

    PMID:12670868

    Open questions at the time
    • How ASH2L specifically contributes to catalysis versus complex assembly was unresolved
    • Which MLL family members associate with ASH2L was not fully catalogued
  4. 2007 High

    Showing that signal-dependent transcription factors recruit ASH2L-containing complexes to target promoters established the principle that ASH2L is a transcriptional coactivator bridging signaling pathways to H3K4 methylation.

    Evidence p38 MAPK-phosphorylated Mef2d recruited Ash2L/MLL to muscle-specific promoters, increasing H3K4me3; validated by ChIP, Co-IP, and RNAi.

    PMID:18026121

    Open questions at the time
    • Whether ASH2L or other COMPASS subunits mediate the TF interaction was unclear
    • Generality across tissues not established
  5. 2011 High

    Crystal structures revealing a winged-helix/forkhead-like DNA-binding domain in ASH2L's N-terminus resolved how this non-catalytic subunit directly engages chromatin independently of histone tail recognition.

    Evidence Two independent X-ray structures plus in vitro DNA-binding assays and ChIP mutagenesis at HOX and β-globin loci showed the WH domain is required for chromatin targeting and H3K4me3.

    PMID:21642971 PMID:21660059

    Open questions at the time
    • DNA sequence or structural preference of the WH domain was not defined
    • Relative contribution of DNA binding versus protein-protein interactions to COMPASS recruitment unclear
  6. 2011 High

    Identification of PRMT1/PRMT5-mediated arginine methylation of ASH2L at R296 revealed that ASH2L itself is subject to cross-regulatory modification by other chromatin-modifying enzymes.

    Evidence In vitro methylation assay with recombinant PRMT1/PRMT5, mass spectrometry identification of R296, and site-directed mutagenesis.

    PMID:21285357

    Open questions at the time
    • Functional consequence of R296 methylation on COMPASS activity or ASH2L localization was not determined
    • Whether this modification occurs genome-wide in vivo was uncharacterized
  7. 2013 High

    Demonstrating that ASH2L's WH domain residue K99 senses H2B ubiquitylation to stimulate H3K4 methylation resolved a key question about how histone crosstalk is mechanistically transduced within MLL complexes.

    Evidence In vitro reconstituted nucleosome methyltransferase assay with K99 mutant abolished H2Bub-stimulated activity for all three H3K4me states.

    PMID:23453805

    Open questions at the time
    • How K99 physically contacts ubiquitin was not structurally resolved
    • Whether this mechanism applies equally to all six SET1/MLL family complexes was untested
  8. 2014 High

    Mapping the Kabuki interaction surface on MLL1 SET domain that contacts the RbBP5/ASH2L heterodimer explained how disease-associated mutations disrupt COMPASS assembly and H3K4 dimethylation.

    Evidence Site-directed mutagenesis of MLL1 KIS residues disrupted MLL1-WRAD interaction and H3K4me2 in vitro.

    PMID:24680668

    Open questions at the time
    • Structural details of the full RbBP5-ASH2L-MLL1 interface at atomic resolution were lacking
    • Impact on H3K4me3 specifically was less clear
  9. 2014 Medium

    Evidence that ASH2L facilitates pre-initiation complex assembly (TFIIB/TFIIF recruitment and Pol II Ser5 phosphorylation) at P53 target promoters revealed its role extends beyond H3K4me3 deposition to direct transcriptional activation mechanics.

    Evidence ChIP at P53 target promoters after ASH2L knockdown showed loss of TFIIB, TFIIF occupancy and Pol II Ser5P, without affecting P53 or Pol II recruitment.

    PMID:25023704

    Open questions at the time
    • Whether PIC stabilization is a general function or specific to P53 targets was unresolved
    • Direct versus indirect mechanism not distinguished
  10. 2018 High

    Structural and genomic analysis of the ASH2L-DPY30 interface revealed that DPY30 stabilizes ASH2L and is required for correct genome-wide placement of H3K4me2/me3 rather than simply boosting catalytic rate.

    Evidence Cryo-EM/structural biochemistry of the ASH2L/DPY30 complex combined with genome-wide ChIP-seq showing DPY30 loss causes persistent aberrant H3K4me2 peaks.

    PMID:30270175

    Open questions at the time
    • Whether DPY30-independent ASH2L functions exist in vivo was unclear
    • Mechanism by which DPY30 directs genomic targeting specificity was not established
  11. 2019 Medium

    A series of conditional knockouts demonstrated that ASH2L is indispensable for hematopoiesis, corticogenesis, and stem cell super-enhancer function, establishing it as a master epigenetic regulator of diverse developmental programs.

    Evidence Hematopoietic KO caused G2 arrest and lethality; neural progenitor KO impaired Wnt targets (rescued by β-catenin); ESC studies showed ASH2L recruits OCT4/SOX2/NANOG to super-enhancers.

    PMID:31164666 PMID:31315048 PMID:31555818

    Open questions at the time
    • Tissue-specific cofactor dependencies were not systematically compared
    • Whether phenotypes are entirely H3K4me-dependent or involve non-canonical ASH2L functions was unclear
  12. 2022 Medium

    Detailed analysis of ASH2L-dependent chromatin architecture showed that ASH2L loss increases nucleosome occupancy and reduces accessibility at CpG island promoters, and the SDI domain mutually stabilizes DPY30, preventing its proteasomal degradation.

    Evidence Conditional KO MEFs analyzed by ATAC-seq/ChIP-seq; SDI mutagenesis showed three residues essential for DPY30 binding; DPY30 degraded by proteasome without ASH2L.

    PMID:35563756 PMID:36065180 PMID:36513698

    Open questions at the time
    • How H3K4me3 loss leads to increased histone loading mechanistically is unknown
    • Whether CTCF redistribution is a direct or indirect consequence of ASH2L loss was not resolved
  13. 2023 Medium

    Tissue-specific knockouts in spermatocytes, ureteric bud, and neural stem cells revealed that ASH2L-dependent H3K4me3 controls distinct gene regulatory networks (transposon silencing, RET/GFRA1, TGF-β) in each lineage.

    Evidence Germ cell KO showed loss of H3K4me3 at epigenetic silencing genes and LINE1 de-repression causing meiotic arrest; UB KO reduced Ret/Wnt11; NSPC KO identified Onecut2→TGF-β axis rescued by TGF-β inhibition.

    PMID:36758123 PMID:37433907 PMID:39992154

    Open questions at the time
    • Whether ASH2L has lineage-specific interactors that direct these distinct programs is unknown
    • How ASH2L selectively maintains H3K4me3 at silencing pathway genes but not others in germ cells is unresolved
  14. 2025 Medium

    Discovery of a non-canonical ASH2L function—forming a complex with KLF5 and FBXW7 to drive KLF5 ubiquitin-proteasomal degradation independently of H3K4 methylation—expanded ASH2L's functional repertoire beyond histone modification.

    Evidence Mass spectrometry, Co-IP, and ChIP in pulmonary arterial SMCs; conditional KO mouse and SMC-specific overexpression rat showed ASH2L loss increases KLF5 and NOTCH3.

    PMID:39996311

    Open questions at the time
    • Whether H3K4me-independent functions occur in other cell types is unknown
    • Structural basis of the ASH2L-KLF5-FBXW7 ternary complex is not defined
    • Whether other COMPASS subunits participate in this non-canonical function is untested
  15. 2025 Medium

    Identification of lysine lactylation at K312 by AARS1 (written) and HDAC1 (erased) revealed a new metabolic input regulating ASH2L chromatin occupancy and VEGFA-driven tumor angiogenesis.

    Evidence High-throughput lactylation proteomics, mutagenesis of K312, ChIP showing K312-lac enhances ASH2L/MLL recruitment to VEGFA; in vivo HCC tumor models.

    PMID:40726441

    Open questions at the time
    • Genome-wide scope of K312-lac-dependent ASH2L redistribution is undefined
    • Whether lactylation and arginine methylation at R296 interact is unknown
    • Independent validation in non-HCC systems is needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of ASH2L's DNA sequence/structure selectivity, how ASH2L coordinates its multiple post-translational modifications (R296me, K312lac) to tune COMPASS activity, and the full extent of H3K4me-independent ASH2L functions across tissues.
  • No high-resolution structure of full-length ASH2L within a complete COMPASS-nucleosome complex
  • Systematic mapping of ASH2L PTM crosstalk is lacking
  • Non-canonical (methylation-independent) functions only demonstrated in one cell type

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0098772 molecular function regulator activity 3 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 5 GO:0005694 chromosome 2
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-4839726 Chromatin organization 6 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1640170 Cell Cycle 3
Partners
DPY30FBXW7GATA3HCF1KLF5MYCRBBP5WDR5
Complex memberships
COMPASS (SET1/MLL family complexes)WRAD subcomplex (WDR5-RBBP5-ASH2L-DPY30)

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 The yeast Ash2 homologue Bre2 is a component of the Set1 complex (Set1C), which methylates histone H3 lysine 4; Set1 is required for complex integrity and Ash2/Bre2 association is essential for this H3K4 methyltransferase activity. Biochemical purification of Set1C from S. cerevisiae, mass spectrometry, in vitro histone methyltransferase assay The EMBO journal High 11742990
2003 Human ASH2L is a core subunit of a Set1/Ash2 histone methyltransferase complex that methylates histone H3 at Lys4 (H3K4me); this activity is blocked if the neighboring K9 is already methylated. HCF-1 tethers this Set1/Ash2L HMT complex together with the Sin3 HDAC complex, and VP16 selectively associates with HCF-1 bound to Set1/Ash2L in the absence of Sin3. Co-immunoprecipitation, in vitro histone methyltransferase assay, GST pulldown Genes & development High 12670868
1998 Drosophila ASH2 exists in a distinct ~500 kDa protein complex separate from the BRM chromatin-remodeling complex and the ASH1 complex, establishing ASH2 as a component of a dedicated multiprotein assembly. Biochemical fractionation and purification from Drosophila embryos, SDS-PAGE analysis Development (Cambridge, England) Medium 9735357
2007 p38 MAPK signaling phosphorylates the transcriptional regulator Mef2d, which then recruits Ash2L-containing methyltransferase complexes to muscle-specific gene promoters, leading to H3K4me3 and gene activation during differentiation. ChIP, Co-IP, in vitro kinase assay, RNAi knockdown with gene expression readout Nature structural & molecular biology High 18026121
2011 Crystal structure of the N-terminal domain of human ASH2L revealed an atypical PHD finger lacking histone tail-binding activity and an unexpected winged-helix (WH) motif that directly binds DNA; DNA-binding-deficient mutants reduced ASH2L localization to the HOX locus and a single mutation (K131A) disrupted chromatin domain boundaries. X-ray crystallography, in vitro DNA-binding assay, mutagenesis, ChIP EMBO reports High 21660059
2011 Crystal structure of ASH2L revealed a forkhead-like helix-wing-helix (HWH) domain that binds DNA; in vivo, the HWH domain is required for binding to the β-globin locus control region, H3K4 trimethylation, and maximal β-globin gene expression. X-ray crystallography, in vitro DNA-binding assay, ChIP, gene expression analysis Nature structural & molecular biology High 21642971
2013 ASH2L in the MLL complex is essential for H2B ubiquitylation (H2Bub)-dependent H3K4 methylation in higher eukaryotes. The N-terminal winged-helix (WH) motif of ASH2L, specifically K99, is required for crosstalk; deletion or mutation of K99 abrogates H2Bub-stimulated MLL activity. Trans-regulation by ubiquitin promotes MLL activity for all three methylation states. In vitro histone methyltransferase assay, site-directed mutagenesis, domain deletion, nucleosome reconstitution Molecular cell High 23453805
2011 PRMT1 (and PRMT5) methylates Ash2L on Arg-296 both in vitro and in cells, representing the first identified post-translational modification on the Ash2L protein and demonstrating cross-talk between chromatin-modifying complexes. In vitro methylation assay with recombinant PRMT1/PRMT5, mass spectrometry, site-directed mutagenesis The Journal of biological chemistry High 21285357
2014 A non-active-site surface on the MLL1 SET domain (the Kabuki interaction surface, KIS) is required for interaction with the RbBP5/Ash2L heterodimer within core MLL family complexes; Kabuki syndrome-associated mutations on this surface disrupt MLL1-WRAD interaction and abolish H3K4 dimethylation by the core complex. In vitro histone methyltransferase assay, Co-IP/pulldown, site-directed mutagenesis mapped to crystal structure Journal of molecular biology High 24680668
2010 Ash2l physically interacts with Tbx1 in both yeast two-hybrid and mammalian cells (Co-IP), and acts as a transcriptional co-activator in luciferase reporter assays; Ash2l-null mouse embryos die early in gestation, demonstrating an essential role in early embryogenesis. Yeast two-hybrid, Co-IP, luciferase reporter assay, knockout mouse Experimental biology and medicine (Maywood, N.J.) Medium 20463296
2010 The trithorax group protein Ash2l is recruited to the inactive X chromosome (Xi) concomitantly with SAF-A and macroH2A at the transition to Xi maintenance; recruitment is triggered by Xist RNA and is mechanistically separable from gene silencing, suggesting Ash2l helps establish a repressive chromatin compartment on non-genic chromatin. Immunofluorescence, RNA FISH, live-cell imaging, mutant Xist RNA expression, fractionation Development (Cambridge, England) Medium 20150277
2011 In C. elegans, ASH-2 (Ash2L ortholog) and SET-2 (Set1 ortholog) are differentially required for H3K4 trimethylation and dimethylation in embryos versus adult germ cells: in embryos, H3K4me3 requires both SET-2 and ASH-2 while H3K4me2 relies mostly on ASH-2; in adult germ cells SET-2 serves a major role while ASH-2 is dispensable. RNAi/genetic knockout, Western blot for bulk H3K4 methylation, immunostaining in different developmental stages Proceedings of the National Academy of Sciences of the United States of America Medium 21527717
2011 In Drosophila wing imaginal discs, ASH2 occupancy correlates with phosphorylated forms of RNA Pol II and H3K4me3; loss of ash2 reduces both RNA Pol II Ser5 phosphorylation and H3K4me3, suggesting a role for ASH2 in transcriptional pausing control. ChIP-seq, genome-wide occupancy analysis, ash2 mutant analysis Nucleic acids research Medium 21310711
2008 Ap2delta interacts with Ash2l via yeast two-hybrid and in mammalian cells; this complex associates with MLL2 (ALR) and methylates H3K4. Ap2delta is required for recruitment of Ash2l and ALR to the Hoxc8 locus, leading to H3K4me3 and gene activation. Yeast two-hybrid, Co-IP, in vitro HMT assay, ChIP Proceedings of the National Academy of Sciences of the United States of America Medium 18495928
2012 Ash2l RNAi knockdown in mouse ES cells reduces global H3K4 methylation and drives cells toward a silenced chromatin state with high H3K9 trimethylation; genome-wide ChIP-seq shows Ash2l is enriched at genes implicated in open chromatin regulation including Chd7, c-Myc, and Kdm4c. RNAi knockdown, ChIP-seq, immunoblot for histone marks The Journal of biological chemistry Medium 23239880
2014 ASH2L and MYC interact directly in vitro and co-localize in cells and on chromatin; MYC associates with H3K4 methyltransferase activity in an ASH2L-dependent manner and stimulates demethylation/acetylation of H3K27, coordinating bivalent chromatin regulation. In vitro binding assay, Co-IP, ChIP, genome-wide ChIP analysis Nucleic acids research Medium 24782528
2011 NF-Y recruits Ash2L (but not MLL1 or WDR5) to CCAAT-containing promoters to deposit H3K4me3; knockdown of NF-Y subunits prevents Ash2L promoter association and dramatically reduces H3K4me3, while endogenous NF-Y and Ash2L specifically interact in vivo. ChIP (with RNAi knockdown), Co-IP, gene expression profiling PloS one Medium 21445285
2012 In Drosophila, Ash2 interacts with the H3K4 methyltransferase Trr and is required for its stabilization; ash2 mutants show defects in ecdysone-responsive gene activation and lack H3K4me3 marks at those loci, establishing Ash2 as an ecdysone receptor coactivator through Trr stabilization. Co-IP, genetic mutant analysis, immunostaining for H3K4me3, gene expression analysis Molecular biology of the cell Medium 23197473
2014 Ash2L is recruited to pro-apoptotic P53 target promoters upon P53 stabilization, enriched with H3K4me3; Ash2L overexpression enhances P53-dependent apoptosis while Ash2L knockdown abrogates P53 target gene expression without affecting P53 or RNAP II recruitment, but reduces RNAP II Ser5-CTD phosphorylation and promoter occupancy of TFIIB and TFIIF, indicating Ash2L aids stable transcription pre-initiation complex formation. ChIP, RNAi knockdown, overexpression, apoptosis assay Oncogene Medium 25023704
2014 ASH2L is recruited to the enhancer of the ERα gene through direct interaction with GATA3, acting as a transcriptional coactivator; forced expression of ASH2L induced ERα expression while depletion suppressed it, with GATA3 identified as the ASH2L-binding protein by Co-IP. Co-IP, ChIP, overexpression/knockdown, luciferase reporter The Journal of biological chemistry Medium 25258321
2018 Structural analysis of the Ash2L/Dpy-30 complex reveals that the extensive interaction network at the Ash2L-Dpy30 interface is critical for correct genome-wide placement of H3K4me2 and H3K4me3 but only modestly contributes to in vitro methyltransferase activity; Dpy-30 loss results in persistent H3K4me2 peaks at highly transcribed regions linked to RNA Pol II cycling. Structural analysis (cryo-EM/biochemistry), genome-wide ChIP-seq, in vitro HMT assay Structure (London, England : 1993) High 30270175
2018 OCT4 directly activates expression of Ash2l-b (a major ASH2L isoform in ESCs); ASH2L-B is required for somatic cell reprogramming and H3K4 methylation during reprogramming. Disruption of WWP2-mediated OCT4 ubiquitination elevates OCT4 stability and H3K4 methylation levels. ChIP, Co-IP, overexpression/knockdown, reprogramming efficiency assay Stem cell reports Medium 30269953
2019 Ash2l directly binds to super-enhancers of stemness genes and recruits Oct4/Sox2/Nanog (OSN) to form an Ash2l/OSN complex; Ash2l knockdown abolishes OSN recruitment to all super-enhancers. A W118A mutation disrupting the Ash2l-Oct4 interaction fails to rescue enhancer activation in Ash2l-depleted cells. ChIP, CRISPRi, mutagenesis, Co-IP, gene expression analysis Nucleic acids research Medium 31555818
2019 ASH2L loss in murine neural progenitor cells impairs H3K4me3 and transcription of Wnt-β-catenin target genes, inhibiting NPC proliferation; overexpressing β-catenin after ASH2L elimination rescues the proliferation deficiency, placing ASH2L upstream of Wnt signaling in corticogenesis. Conditional knockout mouse, ChIP, RNA-seq, β-catenin rescue experiment Cell reports Medium 31315048
2019 Targeted disruption of Ash2l in the murine hematopoietic system causes global reduction of H3K4 methylation, down-regulation of mitosis-associated genes, G2-phase accumulation of LSK cells, and failure of hematopoietic stem/progenitor cell proliferation and differentiation, leading to mouse death. Conditional knockout mouse, flow cytometry, RNA-seq, immunoblot for H3K4 methylation Scientific reports Medium 31164666
2019 ASH2L associates with ERα and is recruited to cis-regulatory elements of PAX2, altering H3K4me3 and H3K27me3 levels to enhance ERα-mediated transactivation; depletion of ASH2L suppresses estrogen-induced target gene expression and inhibits endometrial cancer cell proliferation/migration. Co-IP, ChIP, RNAi knockdown, gene expression analysis Cancer science Medium 32279431
2022 Upon loss of Ash2l in mouse embryo fibroblasts, H3K4 methylation and gene expression are downregulated; cells undergo senescence with a signature set of downregulated FoxM1-responsive genes, and exogenous FOXM1 is sufficient to delay senescence, placing Ash2l upstream of FoxM1-dependent gene expression required for cell cycle progression. Conditional KO MEFs, ChIP-seq, RNA-seq, FOXM1 rescue experiment, senescence assays Nucleic acids research Medium 35819198
2022 Loss of Ash2l in mouse embryo fibroblasts reduces H3K4me1 and H3K4me3 at promoters, increases histone H3 loading, and reduces chromatin accessibility at CpG island promoters; it also alters CTCF binding distribution, demonstrating that Ash2l-dependent H3K4me3 is necessary for maintaining promoter chromatin accessibility. Conditional KO MEFs, ATAC-seq, ChIP-seq for multiple histone marks and CTCF, RNA-seq Scientific reports Medium 36513698
2022 DPY30 functions as an ASH2L-specific stabilizer: it increases ASH2L stability and enhances ASH2L-mediated interactions, promoting compaction and stabilization of the MLL1 complex. DPY30-stabilized ASH2L acquires additional interfaces with H3 and nucleosomal DNA, boosting methyltransferase activity on nucleosomes. In vitro HMT assay, structural biochemistry, Co-IP, stability assays iScience High 36065180
2022 The ASH2L SDI (Sdc1-DPY30 interaction) domain is required for binding and stabilizing DPY30; three specific amino acids in SDI are essential for DPY30 recognition. Without ASH2L, DPY30 is degraded via the ubiquitin-proteasomal pathway. Conditional KO mouse model, mutagenesis, Co-IP, proteasome inhibitor experiments, ChIP-seq, RNA-seq Cells Medium 35563756
2022 Ash2l and Dpy30 interact with neural plate border transcription factors (Msx1, Tfap2a) in Xenopus; ASH2L and H3K4me3 accumulate at the sox10 promoter in a Tfap2a-dependent manner, and ash2l knockdown impairs neural crest marker expression, placing Ash2l as a COMPASS recruiter for neural crest specification. Co-IP (Xenopus), ChIP, morpholino knockdown, gene expression analysis Developmental biology Medium 36162552
2023 In glioblastoma, mass spectrometry revealed ASH2L interaction partners including SETD1A, SETD1B, MLL1, and MLL2; ASH2L depletion downregulates cell cycle genes (TRA2B, BARD1, KIF20B, ARID4A, SMARCC1) and leads to cell cycle arrest and apoptosis. CRISPR/Cas9 screen, mass spectrometry, RNA-seq, greenCUT&RUN, KO phenotype Cell communication and signaling : CCS Medium 37974198
2023 ASH2L-mediated H3K4me3 at the HIPK2 and ADAM17 promoters activates their transcription, leading to aberrant Notch1 signaling pathway activation; ASH2L loss in db/db mice reduces glomerular injury and fibrosis, establishing the ASH2L→HIPK2→Notch1 axis in diabetic nephropathy. Conditional KO mouse, ChIP, RNA-seq, in vivo phenotype analysis Translational research : the journal of laboratory and clinical medicine Medium 37879562
2023 Ash2l deficiency in neural stem/progenitor cells impairs proliferation and differentiation; Onecut2 is a major downstream target of ASH2L, regulated by bivalent histone modifications. Onecut2 modulates TGF-β signaling, and a TGF-β inhibitor rescues the Ash2l-deficient NSPC phenotype, establishing an ASH2L→Onecut2→TGF-β signaling axis. Conditional KO mouse, RNA-seq, ChIP, rescue experiments with Onecut2 overexpression and TGF-β inhibitor Cell death and differentiation Medium 37433907
2023 ASH2L promotes invasion and migration of triple-negative breast cancer cells; it regulates IL1B expression directly through interaction with COMPASS components and H3K4 methylation at IL1B genomic regions. Co-IP, ChIP, RNA-seq, invasion/migration assays with KD Biochemical and biophysical research communications Medium 37262949
2023 In meiotic spermatocytes, Ash2l deficiency causes global loss of H3K4me3 at promoters and decreases expression of genes involved in epigenetic silencing pathways (H3K9me2, DNA methylation, piRNA), leading to ectopic LINE1-ORF1P expression, failure of chromosomal synapsis, and meiotic arrest; Ash2l is dispensable for mitosis in differentiated spermatogonia. Germ cell-specific KO mouse, ChIP-seq, RNA-seq, immunostaining, meiotic spread analysis Development (Cambridge, England) Medium 39992154
2023 Ureteric bud-specific inactivation of Ash2l causes deficient H3K4 trimethylation, reduced cell proliferation at the UB tip, and downregulation of Ret, Gfra1, and Wnt11, placing ASH2L-dependent H3K4me3 upstream of RET/GFRA1 signaling in ureteric bud morphogenesis. Conditional KO mouse, RNA-seq, CUT&TAG sequencing, ChIP Journal of the American Society of Nephrology : JASN Medium 36758123
2023 ASH2L upregulation in diabetic endothelial cells activates STEAP4 transcription via H3K4me3; STEAP4-mediated copper uptake via CTR1 triggers oxidative stress and inflammation. Endothelial-specific Ash2l knockdown in db/db mice restores vascular function, establishing an ASH2L→STEAP4→copper uptake axis in diabetic endothelial dysfunction. AAV-shRNA KD in vivo, ChIP, Co-IP, endothelium-dependent relaxation assays Acta pharmacologica Sinica Medium 37903897
2025 In pulmonary arterial smooth muscle cells, ASH2L forms a protein complex with KLF5 and FBXW7, accelerating ubiquitin-proteasomal degradation of KLF5, thereby reducing NOTCH3 transcription; this mechanism is independent of canonical H3K4me3-based transcriptional activation. ASH2L deficiency promotes KLF5 recruitment to the NOTCH3 promoter, enhancing NOTCH3 expression and SMC proliferation. Mass spectrometry, Co-IP, ChIP, conditional KO mouse and SMC-specific overexpression rat, pharmacological KLF5 blockade Circulation research Medium 39996311
2025 Lysine 312 lactylation (K312-lac) of ASH2L is mediated by AARS1 (writer) and HDAC1 (eraser); ASH2L-K312-lac promotes enrichment at VEGFA genomic regions and recruitment of the MLL complex, enhancing VEGFA expression and tumor angiogenesis in hepatocellular carcinoma. High-throughput proteomics, Co-IP, ChIP, mutagenesis, in vivo tumor models Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 40726441
2019 ASH2L-derived cell-penetrating peptides targeting the DPY30-binding groove specifically inhibit DPY30's interaction with ASH2L and H3K4 methylation enhancement, demonstrating that the ASH2L-DPY30 interface is functionally critical for H3K4 methylation and MLL-rearranged leukemia cell growth. Competitive peptide binding assay, H3K4 methylation assay, cell viability assay Experimental cell research Medium 31251903
2019 ASH2L directly associates with ERα and is recruited with ERα to the BCL2L1 (BCL-XL) locus; glucocorticoid receptor (uGR) and ASH2L interact in a common complex at the BCL2L1 promoter/HRE through chromatin looping. Dexamethasone reduces GR and ASH2L recruitment, diminishing BCL-XL expression and inducing apoptosis. Co-IP, ChIP, chromatin conformation capture, siRNA knockdown Biochimica et biophysica acta. Gene regulatory mechanisms Medium 31870784
2024 Ash2l promotes scavenger receptor (CD36, SR-A) transcription by catalyzing H3K4me3 at the PPARγ promoter and triggers pro-inflammatory NF-κB activation by enhancing CD36-TLR4 interaction; endothelial-specific Ash2l knockdown in ApoE-/- mice reduces atherosclerotic lesion formation. In vivo AAV-shRNA KD in ApoE-/- mice, ChIP, Co-IP, lipid uptake assays Cellular and molecular life sciences : CMLS Medium 38280036
2004 Drosophila ASH2 directly binds Skittles (SKTL), a phosphatidylinositol 4-phosphate 5-kinase; biochemical evidence of direct interaction and genetic evidence of functional significance were provided, with both ash2 and sktl mutants showing dramatically increased histone H1 hyperphosphorylation. Biochemical binding assay (pulldown), genetic interaction analysis, immunostaining of polytene chromosomes Genetics Low 15280236
2014 Depletion of WAR subcomplex components (WDR5, ASH2L, RBBP5) increases levels of unspliced transcripts of immediate early genes (e.g., FOS) without necessarily changing mature transcript levels or H3K4me3 at promoters, revealing a role for the WAR subcomplex in efficient pre-mRNA processing/splicing. RNAi knockdown, RT-PCR for unspliced vs. mature transcripts, ChIP Cellular & molecular biology letters Low 24715476

Source papers

Stage 0 corpus · 77 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 The Saccharomyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone 3 lysine 4. The EMBO journal 502 11742990
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
1998 The Drosophila trithorax group proteins BRM, ASH1 and ASH2 are subunits of distinct protein complexes. Development (Cambridge, England) 239 9735357
2007 p38 MAPK signaling regulates recruitment of Ash2L-containing methyltransferase complexes to specific genes during differentiation. Nature structural & molecular biology 174 18026121
1989 The ash-1, ash-2 and trithorax genes of Drosophila melanogaster are functionally related. Genetics 115 2497049
2010 The Trithorax group protein Ash2l and Saf-A are recruited to the inactive X chromosome at the onset of stable X inactivation. Development (Cambridge, England) 99 20150277
2011 Caenorhabditis elegans chromatin-associated proteins SET-2 and ASH-2 are differentially required for histone H3 Lys 4 methylation in embryos and adult germ cells. Proceedings of the National Academy of Sciences of the United States of America 90 21527717
2009 H3K4 dimethylation in hepatocellular carcinoma is rare compared with other hepatobiliary and gastrointestinal carcinomas and correlates with expression of the methylase Ash2 and the demethylase LSD1. Human pathology 78 19896696
2019 Circ-ASH2L promotes tumor progression by sponging miR-34a to regulate Notch1 in pancreatic ductal adenocarcinoma. Journal of experimental & clinical cancer research : CR 77 31718694
2010 Ash2l interacts with Tbx1 and is required during early embryogenesis. Experimental biology and medicine (Maywood, N.J.) 67 20463296
2013 ASH2L regulates ubiquitylation signaling to MLL: trans-regulation of H3 K4 methylation in higher eukaryotes. Molecular cell 65 23453805
1996 Molecular genetic analysis of Drosophila ash2, a member of the trithorax group required for imaginal disc pattern formation. Genetics 63 8889525
2012 The trithorax group protein Ash2l is essential for pluripotency and maintaining open chromatin in embryonic stem cells. The Journal of biological chemistry 55 23239880
2014 The interaction of MYC with the trithorax protein ASH2L promotes gene transcription by regulating H3K27 modification. Nucleic acids research 44 24782528
2011 Crystal structure of the N-terminal region of human Ash2L shows a winged-helix motif involved in DNA binding. EMBO reports 42 21660059
2014 A non-active-site SET domain surface crucial for the interaction of MLL1 and the RbBP5/Ash2L heterodimer within MLL family core complexes. Journal of molecular biology 39 24680668
2011 Crystal structure of the trithorax group protein ASH2L reveals a forkhead-like DNA binding domain. Nature structural & molecular biology 37 21642971
2017 Diverse roles of WDR5-RbBP5-ASH2L-DPY30 (WRAD) complex in the functions of the SET1 histone methyltransferase family. Journal of biosciences 33 28229975
2011 Genome-wide chromatin occupancy analysis reveals a role for ASH2 in transcriptional pausing. Nucleic acids research 33 21310711
2008 Transcription factor Ap2delta associates with Ash2l and ALR, a trithorax family histone methyltransferase, to activate Hoxc8 transcription. Proceedings of the National Academy of Sciences of the United States of America 30 18495928
2007 Functional dissection of the ash2 and ash1 transcriptomes provides insights into the transcriptional basis of wing phenotypes and reveals conserved protein interactions. Genome biology 30 17466076
2004 The direct interaction between ASH2, a Drosophila trithorax group protein, and SKTL, a nuclear phosphatidylinositol 4-phosphate 5-kinase, implies a role for phosphatidylinositol 4,5-bisphosphate in maintaining transcriptionally active chromatin. Genetics 30 15280236
2018 Disruption of OCT4 Ubiquitination Increases OCT4 Protein Stability and ASH2L-B-Mediated H3K4 Methylation Promoting Pluripotency Acquisition. Stem cell reports 28 30269953
2011 Protein-arginine methyltransferase 1 (PRMT1) methylates Ash2L, a shared component of mammalian histone H3K4 methyltransferase complexes. The Journal of biological chemistry 28 21285357
2018 Structural Analysis of the Ash2L/Dpy-30 Complex Reveals a Heterogeneity in H3K4 Methylation. Structure (London, England : 1993) 27 30270175
2019 The COMPASS Family Protein ASH2L Mediates Corticogenesis via Transcriptional Regulation of Wnt Signaling. Cell reports 26 31315048
2019 Ash2l interacts with Oct4-stemness circuitry to promote super-enhancer-driven pluripotency network. Nucleic acids research 26 31555818
1999 Cloning and characterization of ASH2L and Ash2l, human and mouse homologs of the Drosophila ash2 gene. Cytogenetics and cell genetics 25 10393421
2020 ASH2L is involved in promotion of endometrial cancer progression via upregulation of PAX2 transcription. Cancer science 21 32279431
2019 Hematopoietic stem and progenitor cell proliferation and differentiation requires the trithorax protein Ash2l. Scientific reports 21 31164666
2016 Low expression of ASH2L protein correlates with a favorable outcome in acute myeloid leukemia. Leukemia & lymphoma 21 28185526
2019 ZNF479 downregulates metallothionein-1 expression by regulating ASH2L and DNMT1 in hepatocellular carcinoma. Cell death & disease 20 31138789
2014 Ash2L enables P53-dependent apoptosis by favoring stable transcription pre-initiation complex formation on its pro-apoptotic target promoters. Oncogene 20 25023704
2014 Absent, small or homeotic 2-like protein (ASH2L) enhances the transcription of the estrogen receptor α gene through GATA-binding protein 3 (GATA3). The Journal of biological chemistry 19 25258321
2011 NF-Y recruits Ash2L to impart H3K4 trimethylation on CCAAT promoters. PloS one 19 21445285
2003 Transcriptional network controlled by the trithorax-group gene ash2 in Drosophila melanogaster. Proceedings of the National Academy of Sciences of the United States of America 19 12626737
2001 ASH2L: alternative splicing and downregulation during induced megakaryocytic differentiation of multipotential leukemia cell lines. Journal of molecular medicine (Berlin, Germany) 19 11466562
2019 Specific inhibition of DPY30 activity by ASH2L-derived peptides suppresses blood cancer cell growth. Experimental cell research 18 31251903
2012 Ash2 acts as an ecdysone receptor coactivator by stabilizing the histone methyltransferase Trr. Molecular biology of the cell 16 23197473
2009 Fgfr3 is a transcriptional target of Ap2delta and Ash2l-containing histone methyltransferase complexes. PloS one 16 20046871
2004 Activation and repression activities of ash2 in Drosophila wing imaginal discs. Development (Cambridge, England) 16 15371308
2023 ASH2L upregulation contributes to diabetic endothelial dysfunction in mice through STEAP4-mediated copper uptake. Acta pharmacologica Sinica 14 37903897
2017 Somatic cancer mutations in the MLL1 histone methyltransferase modulate its enzymatic activity and dependence on the WDR5/RBBP5/ASH2L complex. Molecular oncology 14 28182322
2016 FLP-4 neuropeptide and its receptor in a neuronal circuit regulate preference choice through functions of ASH-2 trithorax complex in Caenorhabditis elegans. Scientific reports 14 26887501
2025 ASH2L-K312-Lac Stimulates Angiogenesis in Tumors to Expedite the Malignant Progression of Hepatocellular Carcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 13 40726441
2015 EGFR promoter exhibits dynamic histone modifications and binding of ASH2L and P300 in human germinal matrix and gliomas. Epigenetics 11 25996283
2002 The ash2 gene is involved in Drosophila wing development. The International journal of developmental biology 11 12068954
2022 Induction of senescence upon loss of the Ash2l core subunit of H3K4 methyltransferase complexes. Nucleic acids research 10 35819198
2022 Loss of the Ash2l subunit of histone H3K4 methyltransferase complexes reduces chromatin accessibility at promoters. Scientific reports 10 36513698
2020 ASH2L drives proliferation and sensitivity to bleomycin and other genotoxins in Hodgkin's lymphoma and testicular cancer cells. Cell death & disease 10 33257682
2009 Homology of dipteran bristles and lepidopteran scales: requirement for the Bombyx mori achaete-scute homologue ASH2. Genetics 10 19667136
2023 ASH2L regulates postnatal neurogenesis through Onecut2-mediated inhibition of TGF-β signaling pathway. Cell death and differentiation 9 37433907
2023 ASH2L-mediated H3K4me3 drives diabetic nephropathy through HIPK2 and Notch1 pathway. Translational research : the journal of laboratory and clinical medicine 9 37879562
2023 Epigenetic-focused CRISPR/Cas9 screen identifies (absent, small, or homeotic)2-like protein (ASH2L) as a regulator of glioblastoma cell survival. Cell communication and signaling : CCS 9 37974198
2023 ASH2L Controls Ureteric Bud Morphogenesis through the Regulation of RET/GFRA1 Signaling Activity in a Mouse Model. Journal of the American Society of Nephrology : JASN 8 36758123
2022 ASH2L Aggravates Fibrosis and Inflammation through HIPK2 in High Glucose-Induced Glomerular Mesangial Cells. Genes 8 36553510
2014 WDR5, ASH2L, and RBBP5 control the efficiency of FOS transcript processing. Cellular & molecular biology letters 8 24715476
2024 Functional role of Ash2l in oxLDL induced endothelial dysfunction and atherosclerosis. Cellular and molecular life sciences : CMLS 7 38280036
2023 ASH2L, a COMPASS core subunit, is involved in the cell invasion and migration of triple-negative breast cancer cells through the epigenetic control of histone H3 lysine 4 methylation. Biochemical and biophysical research communications 7 37262949
2023 CSTF2T facilitates pancreatic adenocarcinoma growth and metastasis by elevating H3K4Me1 methylation of CALB2 via ASH2L. Cancer biology & therapy 7 37287122
2022 DPY30 acts as an ASH2L-specific stabilizer to stimulate the enzyme activity of MLL family methyltransferases on different substrates. iScience 7 36065180
2020 Lack of the Histone Methyltransferase Gene Ash2 Results in the Loss of Citrinin Production in Monascus purpureus. Journal of food protection 7 32221575
2019 Glucocorticoids uncover a critical role for ASH2L on BCL-X expression regulation in leukemia cells. Biochimica et biophysica acta. Gene regulatory mechanisms 7 31870784
2023 ASH2L, Core Subunit of H3K4 Methylation Complex, Regulates Amelogenesis. Journal of dental research 6 37990471
2022 Ash2l, an obligatory component of H3K4 methylation complexes, regulates neural crest development. Developmental biology 5 36162552
2025 ASH2L Deficiency in Smooth Muscle Drives Pulmonary Vascular Remodeling. Circulation research 2 39996311
2024 ASH2L Mediates Epidermal Differentiation and Hair Follicle Morphogenesis through H3K4me3 Modification. The Journal of investigative dermatology 2 38582368
2022 The Ash2l SDI Domain Is Required to Maintain the Stability and Binding of DPY30. Cells 2 35563756
2018 Expression specificity and compensation effect of Ash2l-1/Ash2l-2 in mouse embryonic stem cells. Yi chuan = Hereditas 2 29576547
2017 [Role of ash2 (absent, small, or homeotic)-like and Jumonji domain-containing protein 3 on histone methylation of interferon-gamma gene and their associations with vascular damage of Kawasaki disease]. Zhonghua xin xue guan bing za zhi 2 29036979
2025 The KMT2 complex protein ASH2L is required for meiotic prophase progression but dispensable for mitosis in differentiated spermatogonia. Development (Cambridge, England) 1 39992154
2025 Drosophila COMPASS Complex Subunits Set1 and Ash2 Are Required for Oocyte Determination and Maintenance of the Synaptonemal Complex. Journal of developmental biology 1 40843898
2026 COMPASS subunit Bre2 regulates chromatin remodeler Arp9 to control Aspergillus flavus aflatoxin synthesis and virulence. Nature communications 0 41720806
2026 ASH2L induces tamoxifen resistance via H3K4me3 dependent ITGA6/ERK signaling in ER-positive breast cancer. British journal of cancer 0 41735581
2026 Disrupting the ASH2L-DPY30 PPI in cancer: structure, function, and therapeutic opportunities in H3K4 methylation. Epigenetics & chromatin 0 41864982
2026 Ash2l deficiency impairs adipose tissue thermogenesis and exacerbates obesity in mice. Cellular & molecular biology letters 0 41872744
2014 [Ash2, a subunit of histone H3K4 methyltransferase complex, is involved in the sporulation in Schizosaccharomyces pombe]. Yi chuan = Hereditas 0 25252312