Affinage

ASH2L

Set1/Ash2 histone methyltransferase complex subunit ASH2 · UniProt Q9UBL3

Length
628 aa
Mass
68.7 kDa
Annotated
2026-06-09
57 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ASH2L is a core scaffolding and regulatory subunit of the SET1/MLL (COMPASS-family) histone H3K4 methyltransferase complexes that couples chromatin marking to gene activation across embryogenesis, hematopoiesis, neurogenesis, and meiosis (PMID:31164666, PMID:31315048, PMID:39992154). Structurally, its N-terminal forkhead-like winged-helix (HWH) domain binds DNA directly and is required for recruitment to target loci such as the HOX and β-globin regions, H3K4 trimethylation, and chromatin domain demarcation (PMID:21660059, PMID:21642971). Within the WRAD core, ASH2L is essential for H2B-ubiquitylation–dependent trans-stimulation of all three H3K4 methylation states through its WH motif residue K99, and it contributes a non-active-site surface that, with RbBP5, forms a second active site on nucleosomes required for MLL1 dimethylation activity (PMID:23453805, PMID:24680668). Its SDI domain binds and stabilizes DPY30, which in turn stabilizes ASH2L and reciprocally boosts MLL complex compaction and methyltransferase activity on nucleosomes; disrupting this interface dysregulates genome-wide H3K4me2/me3 placement (PMID:30270175, PMID:36065180, PMID:35563756). ASH2L does not act constitutively but is targeted to specific loci by sequence-specific transcription factors and signaling inputs—including Mef2d (downstream of p38 MAPK), Ap2δ, NF-Y, GATA3, MYC, OCT4/SOX2/NANOG, and Tfap2a—to deposit activating H3K4me3 at lineage- and stimulus-specific genes (PMID:18026121, PMID:18495928, PMID:21445285, PMID:24782528, PMID:25258321, PMID:31555818, PMID:36162552). ASH2L is itself post-translationally modified, being arginine-methylated at R296 by PRMT1/PRMT5 and lactylated at K312 by AARS1/HDAC1, the latter directing MLL recruitment to VEGFA for tumor angiogenesis (PMID:21285357, PMID:40726441). Beyond canonical methyltransferase scaffolding, ASH2L supports stable transcription pre-initiation complex assembly at p53 pro-apoptotic targets (PMID:25023704) and acts non-canonically in vascular smooth muscle by forming a KLF5–FBXW7 complex that accelerates KLF5 ubiquitin-proteasomal degradation independently of H3K4me3 (PMID:39996311).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2011 High

    Established the structural basis for how ASH2L engages chromatin directly rather than only as a passive scaffold, by resolving an atypical PHD finger and a DNA-binding winged-helix/HWH domain required for locus targeting and H3K4me3.

    Evidence X-ray crystallography with mutagenesis and ChIP at the HOX and β-globin loci

    PMID:21642971 PMID:21660059

    Open questions at the time
    • Sequence determinants of DNA recognition specificity unresolved
    • Does not establish how DNA binding is integrated with transcription-factor-directed recruitment
  2. 2013 High

    Showed mechanistically why ASH2L is required for the H2Bub–H3K4 methylation crosstalk, defining the WH motif residue K99 as essential for trans-stimulation of all three methylation states.

    Evidence In vitro reconstituted methyltransferase assays with K99 mutagenesis

    PMID:23453805

    Open questions at the time
    • Molecular sensor that transmits the ubiquitin signal to the active site not defined
    • Why MLL3 is unresponsive not explained at residue level
  3. 2014 High

    Defined the ASH2L/RbBP5 heterodimer as forming a second active site on the MLL1 SET domain, explaining a disease-relevant non-active-site interaction surface.

    Evidence Mutagenesis modeled on Kabuki-syndrome mutations with in vitro methyltransferase and Co-IP assays

    PMID:24680668

    Open questions at the time
    • Direct structural visualization of the second active site on nucleosomes not provided
    • Generality across all SET1/MLL members not tested
  4. 2018 High

    Reconciled in vitro versus in vivo roles by showing the DPY30/ASH2L interface governs genome-wide H3K4me placement more than bulk catalytic rate, linking COMPASS kinetics to RNA polymerase cycling.

    Evidence Structural analysis combined with genome-wide ChIP-seq and in vitro methyltransferase assays

    PMID:30270175

    Open questions at the time
    • Causal coupling between Pol II elongation and persistent H3K4me2 peaks not demonstrated
    • Locus-selectivity mechanism unresolved
  5. 2022 High

    Established a reciprocal stabilization mechanism in which DPY30 binds the ASH2L SDI domain to stabilize ASH2L and create new H3/DNA contacts, while ASH2L protects DPY30 from proteasomal degradation.

    Evidence Biochemical reconstitution, SDI-domain mutagenesis, proteasome-inhibition and rescue assays

    PMID:35563756 PMID:36065180

    Open questions at the time
    • DPY30 functions independent of ASH2L only inferred from rescue
    • Stoichiometry of the stabilized complex not defined
  6. 2011 High

    Identified the first post-translational modifications of ASH2L, showing arginine methylation at R296 by PRMT1/PRMT5 and establishing crosstalk between distinct chromatin-modifying enzyme complexes.

    Evidence In vitro methylation, mass spectrometry, and cell-based mutagenesis

    PMID:21285357

    Open questions at the time
    • Functional consequence of R296 methylation for complex activity not resolved
    • Reader of the modification unknown
  7. 2025 Medium

    Extended the regulation of ASH2L to metabolic signaling by showing AARS1/HDAC1-mediated lactylation at K312 directs MLL recruitment to VEGFA to drive angiogenesis.

    Evidence Proteomics-identified PTM validated by ChIP-seq, Co-IP, and in vivo HCC tumor models

    PMID:40726441

    Open questions at the time
    • Single-lab finding without independent confirmation
    • How K312-lac selects VEGFA over other loci not defined
  8. 2011 Medium

    Demonstrated that ASH2L is recruited to specific gene loci by sequence-specific transcription factors and signaling, rather than acting genome-wide indiscriminately, across muscle, developmental, and CCAAT-box promoters.

    Evidence Co-IP, ChIP, reporter and RNAi assays for Mef2d/p38 MAPK, Ap2δ, and NF-Y

    PMID:18026121 PMID:18495928 PMID:20046871 PMID:21445285

    Open questions at the time
    • Direct contact interfaces between ASH2L and most transcription factors not mapped
    • Hierarchy among co-recruited subunits not fully resolved
  9. 2014 Medium

    Broadened ASH2L's role beyond H3K4 methylation to stabilizing the transcription pre-initiation complex at p53 pro-apoptotic genes and coordinating pre-mRNA processing.

    Evidence ChIP for PIC components (Pol II Ser5, TFIIB, TFIIF), RNAi, and splicing RT-PCR

    PMID:24715476 PMID:24782528 PMID:25023704

    Open questions at the time
    • Mechanism linking ASH2L to PIC stabilization independent of H3K4me3 not defined
    • Pre-mRNA processing role rests on a single low-confidence study
  10. 2019 Medium

    Genetic loss-of-function across tissues established ASH2L as essential for stem/progenitor proliferation and differentiation programs via H3K4 methylation and downstream signaling effectors (Wnt-β-catenin, FoxM1, Onecut2/TGF-β, OSN pluripotency).

    Evidence Conditional knockout mice and ES cells with ChIP-seq, RNA-seq, and genetic/pharmacological rescue

    PMID:23239880 PMID:31164666 PMID:31315048 PMID:31555818 PMID:35819198 PMID:37433907

    Open questions at the time
    • Whether developmental phenotypes are fully explained by H3K4me loss versus non-canonical roles not resolved
    • Tissue-specific target gene networks incompletely mapped
  11. 2023 Medium

    Defined ASH2L as essential for meiotic prophase progression, linking its H3K4me3 activity to transposon-repression pathways (H3K9me2, DNA methylation, piRNA) required for chromosomal synapsis.

    Evidence Germ-cell-specific conditional knockout with ChIP-seq, RNA-seq, and immunofluorescence

    PMID:39992154

    Open questions at the time
    • Direct versus indirect control of repressive pathways not separated
    • Mitosis-dispensable but meiosis-essential distinction mechanistically unexplained
  12. 2025 Medium

    Revealed a non-canonical, methyltransferase-independent function of ASH2L in vascular smooth muscle, scaffolding a KLF5–FBXW7 complex to accelerate KLF5 ubiquitin-proteasomal degradation and restrain NOTCH3.

    Evidence Co-IP, mass spectrometry, ubiquitin assays, and conditional KO/overexpression mouse models

    PMID:39996311

    Open questions at the time
    • Single-lab finding awaiting independent confirmation
    • Structural basis of the ASH2L–KLF5–FBXW7 complex unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ASH2L's diverse post-translational modifications, DNA-binding, and transcription-factor partnerships are integrated to achieve locus-specific H3K4 methylation versus its non-canonical degradation and PIC-stabilizing functions remains unresolved.
  • No unifying model distinguishing canonical from non-canonical ASH2L functions
  • Determinants directing ASH2L to specific genomic loci across contexts not defined
  • No timeline evidence linking ASH2L to a defined Mendelian disorder

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0060090 molecular adaptor activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0003677 DNA binding 2 GO:0042393 histone binding 2
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1640170 Cell Cycle 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
DPY30GATA3KLF5MLL1MYCOCT4RBBP5WDR5
Complex memberships
SET1/MLL (COMPASS) H3K4 methyltransferase complexWRAD (WDR5-RBBP5-ASH2L-DPY30) core

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 Crystal structure of the N-terminal domain of ASH2L reveals an atypical PHD finger (without histone tail-binding activity) and a winged-helix (WH) motif that directly binds DNA. DNA-binding-deficient mutants reduced ASH2L localization to the HOX locus, and a single K131A mutation in the WH domain broke chromatin domain boundary, implicating ASH2L in chromosome demarcation. X-ray crystallography, mutagenesis, ChIP EMBO reports High 21660059
2011 Crystal structure of ASH2L reveals 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, mutagenesis, ChIP, gene expression analysis Nature structural & molecular biology High 21642971
2013 ASH2L, via its N-terminal winged-helix (WH) motif (specifically K99), is essential for H2B ubiquitylation (H2Bub)-dependent H3K4 methylation by the MLL complex. Crosstalk between H2Bub and H3K4 methylation can occur in trans (ubiquitin does not need to be on nucleosomes or histones), and promotes MLL activity for all three methylation states. MLL3 does not respond to H2Bub, indicating regulatory specificity among MLL family members. In vitro methyltransferase assay, mutagenesis (K99 deletion/mutation), biochemical reconstitution Molecular cell High 23453805
2014 A non-active-site surface of the MLL1 SET domain (termed the Kabuki interaction surface, KIS) is required for interaction with the RbBP5/Ash2L heterodimer. Mutations at this surface (modeled on Kabuki syndrome MLL2 mutations) abolish H3K4 dimethylation by the MLL1 core complex and disrupt MLL1–WRAD or MLL1–RbBP5/Ash2L interaction, implicating Ash2L in forming a second active site within SET1 family core complexes. Mutagenesis, in vitro methyltransferase assay, co-immunoprecipitation Journal of molecular biology High 24680668
2018 Structural and genome-wide studies reveal that an extensive interaction network at the Dpy-30/Ash2L interface is critical for correct genome-wide placement of H3K4me2 and H3K4me3 but only modestly contributes to in vitro KMT2 methyltransferase activity. H3K4me2 peaks persisting after Dpy-30 loss occur in highly transcribed regions, indicating interplay between COMPASS kinetics and RNA polymerase cycling. Structural analysis, genome-wide ChIP-seq, in vitro methyltransferase assays Structure High 30270175
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 to increase its HKMT activity. DPY30-stabilized ASH2L acquires additional interfaces with H3 and nucleosomal DNA, boosting MLL1 complex methyltransferase activity on nucleosomes. Biochemical reconstitution, in vitro methyltransferase assay, structural/biochemical analysis iScience High 36065180
2011 PRMT1 (and PRMT5) methylate Ash2L on Arg-296 both in vitro and in cells, representing the first post-translational modification identified on Ash2L and demonstrating cross-talk between chromatin-modifying enzyme complexes. In vitro methylation assay, mass spectrometry, mutagenesis, cell-based assay The Journal of biological chemistry High 21285357
2007 Ash2L-containing methyltransferase complexes are recruited to specific muscle-specific gene promoters during differentiation, directed by the transcriptional regulator Mef2d. p38 MAPK signaling phosphorylates Mef2d to modulate this interaction, resulting in H3K4me3 at target promoters and epigenetic marking for gene expression. ChIP, co-immunoprecipitation, signaling pathway analysis (p38 MAPK inhibition/activation) Nature structural & molecular biology High 18026121
2010 Ash2L physically interacts with Tbx1 in both yeast two-hybrid and mammalian co-immunoprecipitation assays, acts as a transcriptional co-activator in luciferase reporter assays, and overlapping expression patterns exist during development. Ash2l-null embryos die early in gestation, demonstrating Ash2l is essential for early embryogenesis. Yeast two-hybrid, co-immunoprecipitation, luciferase reporter assay, gene-trap knockout mouse Experimental biology and medicine Medium 20463296
2008 Ap2delta physically interacts exclusively with Ash2l (identified by yeast two-hybrid), and this interaction mediates Ap2delta transactivation. Ap2delta associates with endogenous ASH2L and MLL2 (ALR) in a complex that methylates H3K4. Ap2delta recruits Ash2l and ALR to the Hoxc8 locus, leading to H3K4me3 and gene activation. Yeast two-hybrid, co-immunoprecipitation, ChIP, luciferase reporter assay PNAS Medium 18495928
2011 NF-Y acts upstream of H3K4me3 deposition by specifically recruiting Ash2L to CCAAT-containing promoters. Knockdown of NF-Y subunits prevents promoter association of Ash2L (but not MLL1 or WDR5), causing a dramatic drop in H3K4me3. Endogenous NF-Y and Ash2L interact in vivo. Additionally, Ash2L knockdown globally reduces H3K4me3 with concomitant increase in H3K79me2. ChIP, RNAi knockdown, co-immunoprecipitation, transcriptional profiling PloS one Medium 21445285
2014 ASH2L and MYC interact directly in vitro and co-localize in cells and on chromatin. MYC associates with H3K4 methyltransferase activity dependent on ASH2L. MYC stimulates demethylation and acetylation of H3K27 through association with KMT2 complexes. WDR5, another KMT2 subunit, also binds directly to MYC. In vitro binding assay, co-immunoprecipitation, ChIP, genome-wide analysis Nucleic acids research Medium 24782528
2010 Ash2L is recruited to the inactive X chromosome (Xi) by Xist RNA concomitantly with Saf-A and macroH2A, characterizing a developmental transition to Xi maintenance. A mutant Xist that does not cause gene repression still triggers Ash2L recruitment and chromosome-wide H4 hypoacetylation, indicating that Ash2L recruitment is mechanistically separable from gene silencing. Immunofluorescence, RNA FISH, cell fractionation, mutant Xist RNA expression Development Medium 20150277
2014 ASH2L is recruited to the enhancer of the ERα (ESR1) gene through GATA3, and acts as a co-activator of GATA3 to promote ERα transcription in breast cancer cells. Depletion of ASH2L suppresses ERα expression; forced expression of ASH2L induces it. Co-immunoprecipitation, ChIP, RNAi knockdown, forced expression assays The Journal of biological chemistry Medium 25258321
2014 Ash2L is required for P53-dependent apoptosis: upon P53 stabilization, pro-apoptotic target promoters are enriched with H3K4me3 and Wdr5, RbBP5, and Ash2L. Ash2L silencing abrogates P53-induced target gene expression and reduces RNA Pol II Ser5-CTD phosphorylation, TFIIB, and TFIIF (RAP74) occupancy, indicating Ash2L aids formation of a stable transcription pre-initiation complex. ChIP, RNAi knockdown, gene expression analysis, overexpression assays Oncogene Medium 25023704
2019 Ash2l directly binds to super-enhancers of stemness genes (Jarid2, Nanog, Sox2, Oct4) and recruits Oct4/Sox2/Nanog (OSN) to form an Ash2l/OSN complex that drives enhancer activation and pluripotency. The W118A mutation disrupting the Ash2l-Oct4 interaction fails to rescue enhancer activation, validating the direct interaction is required. CRISPRi blocking of Ash2l-binding motifs at super-enhancers prevents OSN recruitment. ChIP, co-immunoprecipitation, CRISPRi/dCas9, mutagenesis, gene expression analysis Nucleic acids research Medium 31555818
2019 Loss of Ash2l in the murine hematopoietic system causes global reduction of H3K4 methylation, deregulated gene expression (including downregulation of mitosis-associated genes), accumulation of LSK cells in G2-phase, and failure of hematopoietic stem/progenitor cell proliferation and differentiation. Conditional knockout mouse, flow cytometry, gene expression analysis, H3K4 methylation assays Scientific reports Medium 31164666
2019 ASH2L loss in neural progenitor cells impairs H3K4me3, reduces Wnt-β-catenin signaling transcriptional machinery, inhibits S-phase entry of NPCs, and causes neocortex malformation with fewer neurons. Overexpressing β-catenin after ASH2L elimination rescues the proliferation deficiency, placing ASH2L upstream of Wnt signaling in neurogenesis. Conditional knockout mouse, ChIP, gene expression analysis, epistasis by β-catenin rescue Cell reports Medium 31315048
2022 Loss of Ash2l in mouse embryo fibroblasts (MEFs) causes global reduction of H3K4me1 and H3K4me3, increased histone H3 loading and reduced chromatin accessibility at CpG island promoters, downregulation of FoxM1-responsive genes, and induction of senescence. Exogenous FOXM1 is sufficient to delay senescence. Conditional knockout MEFs, ATAC-seq, ChIP-seq, gene expression analysis, FOXM1 rescue experiment Nucleic acids research Medium 35819198
2022 Loss of Ash2l reduces chromatin accessibility at promoters, increases loading of histone H3, alters activating and repressive histone marks, and alters CTCF binding (lost at promoter-associated sites, gained at intergenic sites), correlating with gene repression. ATAC-seq, ChIP-seq, conditional knockout MEFs Scientific reports Medium 36513698
2022 The ASH2L SDI (Sdc1 DPY30 interaction) domain is required for recognition and binding of DPY30. Loss of Ash2l causes DPY30 degradation via the ubiquitin-proteasomal pathway. Three specific amino acids in the SDI domain are essential for DPY30 binding. Overexpression of DPY30 in Ash2l-depleted cells rescues Ccnd1 expression and abnormal cell cycle, indicating DPY30 can act in other complexes independently of ASH2L. Mouse model, conditional knockout, mutagenesis, proteasome inhibition assay, western blot, ChIP-seq/RNA-seq analysis Cells Medium 35563756
2009 Ap2delta is required for recruitment of Ash2l-containing complexes to the Fgfr3 promoter, and this recruitment leads to H3K4me3 and Fgfr3 transcriptional activation. Ash2l and Ap2delta co-regulate 42 genes identified by genome-wide expression profiling. ChIP, RNAi knockdown, gene expression profiling (microarray) PloS one Medium 20046871
2019 Cell-penetrating peptides derived from ASH2L's DPY30-binding domain specifically inhibit DPY30's interaction with ASH2L and reduce H3K4 methylation in cells, suppressing growth of MLL-rearranged leukemia and MYC-dependent hematologic cancer cells. Peptide competition assay, cell viability assays, H3K4 methylation assays Experimental cell research Medium 31251903
2018 ASH2L-B, a major isoform highly expressed in embryonic stem cells, is directly activated by OCT4 transcription. ASH2L-B is required for somatic cell reprogramming and for H3K4 methylation levels during reprogramming. ChIP, reporter assay, gene knockdown, reprogramming efficiency assay, western blot Stem cell reports Medium 30269953
2020 ASH2L associates with ERα and is recruited to cis-regulatory elements of the PAX2 gene, where it modulates H3K4me3 and H3K27me3 levels to enhance ERα-mediated transactivation. Knockdown of ASH2L reduces PAX2 expression and suppresses endometrial cancer cell proliferation and migration. Co-immunoprecipitation, ChIP, RNAi knockdown, cell proliferation and migration assays Cancer science Medium 32279431
2023 ASH2L is essential for meiotic prophase progression but dispensable for mitosis in differentiated spermatogonia. Ash2l deficiency causes global loss of H3K4me3 at promoters, downregulation of genes in H3K9 di-methylation, DNA methylation and piRNA pathways important for transposon repression, leading to meiotic arrest with failures in chromosomal synapsis and ectopic LINE1-ORF1P expression. Germ cell-specific conditional KO mouse, ChIP-seq, RNA-seq, immunofluorescence Development Medium 39992154
2022 Dpy-30 and Ash2L associate (by co-immunoprecipitation) with neural plate border transcription factors Msx1 and Tfap2a in Xenopus. ChIP demonstrates Ash2L and H3K4me3 accumulate at the sox10 promoter in a Tfap2a-dependent manner, establishing that Ash2l interacts with specific transcription factors to recruit COMPASS to neural crest gene regulatory regions. Co-immunoprecipitation, ChIP, morpholino knockdown Developmental biology Medium 36162552
2023 ASH2L interacts with SET1/MLL family members (SETD1A, SETD1B, MLL1, MLL2) in glioblastoma cells as determined by mass spectrometry. ASH2L depletion leads to cell cycle arrest, apoptosis, and downregulation of cell cycle regulatory genes (TRA2B, BARD1, KIF20B, ARID4A, SMARCC1) as determined by RNA-seq and CUT&RUN. CRISPR/Cas9 screen, mass spectrometry, RNA-seq, CUT&RUN, orthotopic in vivo model Cell communication and signaling Medium 37974198
2023 ASH2L-mediated H3K4me3 at the HIPK2 and ADAM17 promoters triggers their transcription, leading to aberrant activation of Notch1 signaling, contributing to fibrosis and inflammation in diabetic nephropathy. Loss of ASH2L in db/db mice reduces glomerular injury. ChIP, conditional knockout mouse (AAV-shRNA), gene expression analysis Translational research Medium 37879562
2023 ASH2L upregulation activates STEAP4 transcription (via H3K4me3) in endothelial cells, elevating copper uptake through CTR1, triggering oxidative stress and inflammatory responses that cause endothelial dysfunction. Endothelial-specific ASH2L knockdown in db/db mice restores endothelium-dependent relaxation. ChIP, AAV-shRNA knockdown in vivo, cell-based assays, copper transport assays Acta pharmacologica Sinica Medium 37903897
2025 In pulmonary arterial smooth muscle cells, ASH2L deficiency promotes SMC proliferation and vascular remodeling independently of canonical H3K4me3-based transcriptional activation. Instead, ASH2L forms a protein complex with KLF5 and FBXW7, accelerating ubiquitin-proteasomal degradation of KLF5. Loss of ASH2L promotes KLF5 recruitment to the NOTCH3 promoter and enhances NOTCH3 expression. Co-immunoprecipitation, mass spectrometry, ChIP, conditional KO/overexpression mouse, ubiquitin assay Circulation research Medium 39996311
2025 AARS1 and HDAC1 mediate lactylation of ASH2L at lysine 312 (K312-lac). ASH2L-K312-lac is enriched in VEGFA genomic regions, facilitates targeted recruitment of the MLL complex, and enhances VEGFA expression through synergistic activation of enhancers and promoters, promoting tumor angiogenesis in HCC. High-throughput proteomics, ChIP-seq, co-immunoprecipitation, in vivo tumor models Advanced science Medium 40726441
2019 ASH2L promotes ASH2L-mediated H3K4me3 and scavenger receptor (including PPARγ) transcription in endothelial cells, and enhances CD36/TLR4 interaction to activate NF-κB pro-inflammatory signaling. Endothelial-specific Ash2l knockdown reduces atherosclerotic lesion formation in ApoE-/- mice. ChIP, co-immunoprecipitation, AAV-shRNA in vivo knockdown, cell-based assays Cellular and molecular life sciences Medium 38280036
2019 Glucocorticoid receptor (uGR) and ASH2L interact in a common protein complex in myeloid leukemia cells, with uGR and ASH2L binding to BCL2L1 via chromatin looping to maintain BCL-XL over-expression. Upon dexamethasone treatment, GR and ASH2L recruitment is reduced, BCL-XL expression diminishes, and apoptosis is induced. Co-immunoprecipitation, ChIP, chromosome conformation assay, gene expression analysis Biochimica et biophysica acta. Gene regulatory mechanisms Medium 31870784
2014 Depletion of WAR subcomplex components (WDR5, ASH2L, RBBP5) leads to increased levels of unspliced FOS transcripts without necessarily affecting mature transcript levels or H3K4me3 at the promoter, revealing a role for ASH2L in coordinating transcription with efficient pre-mRNA processing. RNAi knockdown, RT-PCR for spliced/unspliced transcripts, ChIP Cellular & molecular biology letters Low 24715476
2012 RNAi knockdown of Ash2l in embryonic stem cells reduces H3K4 methylation levels and drives cells to a silenced chromatin state with elevated H3K9me3. Genome-wide ChIP-seq shows Ash2l is enriched at genes regulating open chromatin, including chromatin remodeler Chd7, c-Myc, and H3K9 demethylase Kdm4c. RNAi knockdown, ChIP-seq, western blot for histone modifications The Journal of biological chemistry Low 23239880
2023 ASH2L-mediated H3K4me3 at the Onecut2 (a bivalent locus) promoter maintains its expression in neural stem/progenitor cells. Loss of Ash2l reduces Onecut2 expression; constitutive Onecut2 expression rescues defective NSPC proliferation and differentiation. Onecut2 modulates TGF-β signaling, and TGF-β inhibitor treatment rectifies the Ash2l-deficient NSPC phenotype. Conditional KO mouse, RNA-seq, ChIP, genetic rescue, pharmacological inhibition Cell death and differentiation Medium 37433907

Source papers

Stage 0 corpus · 57 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 p38 MAPK signaling regulates recruitment of Ash2L-containing methyltransferase complexes to specific genes during differentiation. Nature structural & molecular biology 175 18026121
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
2019 Circ-ASH2L promotes tumor progression by sponging miR-34a to regulate Notch1 in pancreatic ductal adenocarcinoma. Journal of experimental & clinical cancer research : CR 78 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
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 35 28229975
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 31 18495928
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
2025 ASH2L-K312-Lac Stimulates Angiogenesis in Tumors to Expedite the Malignant Progression of Hepatocellular Carcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 19 40726441
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
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
2009 Fgfr3 is a transcriptional target of Ap2delta and Ash2l-containing histone methyltransferase complexes. PloS one 16 20046871
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
2022 Loss of the Ash2l subunit of histone H3K4 methyltransferase complexes reduces chromatin accessibility at promoters. Scientific reports 12 36513698
2022 Induction of senescence upon loss of the Ash2l core subunit of H3K4 methyltransferase complexes. Nucleic acids research 11 35819198
2015 EGFR promoter exhibits dynamic histone modifications and binding of ASH2L and P300 in human germinal matrix and gliomas. Epigenetics 11 25996283
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 10 37974198
2020 ASH2L drives proliferation and sensitivity to bleomycin and other genotoxins in Hodgkin's lymphoma and testicular cancer cells. Cell death & disease 10 33257682
2023 CSTF2T facilitates pancreatic adenocarcinoma growth and metastasis by elevating H3K4Me1 methylation of CALB2 via ASH2L. Cancer biology & therapy 9 37287122
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
2024 Functional role of Ash2l in oxLDL induced endothelial dysfunction and atherosclerosis. Cellular and molecular life sciences : CMLS 8 38280036
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 DPY30 acts as an ASH2L-specific stabilizer to stimulate the enzyme activity of MLL family methyltransferases on different substrates. iScience 8 36065180
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
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
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 3 39996311
2022 The Ash2l SDI Domain Is Required to Maintain the Stability and Binding of DPY30. Cells 3 35563756
2025 The KMT2 complex protein ASH2L is required for meiotic prophase progression but dispensable for mitosis in differentiated spermatogonia. Development (Cambridge, England) 2 39992154
2024 ASH2L Mediates Epidermal Differentiation and Hair Follicle Morphogenesis through H3K4me3 Modification. The Journal of investigative dermatology 2 38582368
2018 Expression specificity and compensation effect of Ash2l-1/Ash2l-2 in mouse embryonic stem cells. Yi chuan = Hereditas 2 29576547
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

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