Affinage

ASH1L

Histone-lysine N-methyltransferase ASH1L · UniProt Q9NR48

Length
2969 aa
Mass
332.8 kDa
Annotated
2026-06-09
73 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ASH1L is a Trithorax-group SET-domain histone methyltransferase that deposits activating histone methylation at active genes and regulatory elements to counteract Polycomb silencing and sustain developmental gene expression programs (PMID:24244179, PMID:39390582). Its catalytic SET domain mono- and dimethylates nucleosomal H3K36, requires intact native nucleosome substrate, and is intrinsically autoinhibited by a post-SET loop that occludes the substrate-binding pocket; mutation of this loop or a second SET-I loop relieves autoinhibition and modulates activity (PMID:21239497, PMID:26292256, PMID:26002201). Activation in cells is achieved when MRG15 binds an FxLP motif N-terminal to the SET domain and recruits ASH1L to nucleosomes via the MRG15 chromodomain, functioning principally as a substrate-recruiting adapter (PMID:30827841, PMID:30827843, PMID:37527654). C-terminal PHD, BAH, and bromodomain modules read H3K4 methylation and bind linker DNA to stabilize chromatin engagement, and the PHD–H3K4me3 interaction feeds back to inhibit H3K36me2 catalysis, establishing intramolecular cross-regulation (PMID:36033518, PMID:40044670). At active and leukemia-associated loci, ASH1L-written H3K36me2 is read by LEDGF to facilitate recruitment of wild-type and fusion MLL complexes, and ASH1L catalytic activity is required for MLL-rearranged leukemic transformation, making its autoinhibitory loop a validated drug target (AS-99) (PMID:27154821, PMID:33990599, PMID:34692539). ASH1L also deposits H3K4 methylation at specific promoters to control diverse physiological programs—enhancing the deubiquitinase A20/Tnfaip3 to restrain NF-κB-driven inflammation, Smad3 to promote Treg polarization, Stac2 in osteoclasts, and synaptic genes in neurons—and supports hematopoietic stem cell quiescence and myoblast fusion (PMID:24012418, PMID:28598443, PMID:38431690, PMID:34782621, PMID:25866973, PMID:30487570). In genome maintenance, DDB2-recruited ASH1L, with MRG15 and FACT, methylates H3K4 at damaged nucleosomes to enable XPC handoff during global-genome nucleotide excision repair (PMID:29109511, PMID:37393406).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2000 Medium

    Established the existence and domain architecture of human ASH1L as a multidomain chromatin protein, raising the question of where it acts in the cell.

    Evidence Immunofluorescence with multiple antibodies, co-labeling with junctional markers, and molecular cloning identifying SET, PHD, AT-hook, and bromodomain modules

    PMID:10860993

    Open questions at the time
    • Enzymatic activity not demonstrated
    • Tight junction localization not mechanistically integrated with later nuclear chromatin functions
  2. 2007 High

    First showed ASH1L is a chromatin-associated methyltransferase at active genes, but assigned its SET domain to H3K4 methylation, leaving substrate specificity unsettled.

    Evidence Genome-wide ChIP, in vitro methyltransferase assay, siRNA knockdown with HoxA10 ChIP, and MLL-null cell lines

    PMID:17923682

    Open questions at the time
    • H3K4 vs H3K36 specificity conflicts with later biochemistry
    • Recruitment mechanism to active genes undefined
  3. 2011 High

    Defined the structural basis of catalysis and reassigned the primary substrate to H3K36, revealing post-SET autoinhibition as a built-in regulatory switch.

    Evidence X-ray crystallography of the catalytic domain, mutagenesis of the autoinhibitory loop, and in vitro methyltransferase assays

    PMID:21239497

    Open questions at the time
    • How autoinhibition is relieved physiologically not yet known
    • Nucleosome substrate requirement not addressed
  4. 2013 High

    Connected ASH1L SET activity to a Polycomb-antagonizing role in development and to direct promoter regulation of inflammatory genes, establishing functional readouts of its catalysis.

    Evidence Ash1l-knockout ES cells with DRB treatment and ChIP-seq (H3K36me2 at Hox loci); ChIP, SET-mutant rescue, and Co-IP at the Tnfaip3/A20 promoter in macrophages

    PMID:24012418 PMID:24244179

    Open questions at the time
    • Recruitment factors directing ASH1L to specific loci not identified
    • Distinction between transcription-coupled and uncoupled methylation incomplete
  5. 2015 High

    Established that robust ASH1L activity depends on native nucleosome substrate and on coordinated SET-domain loop dynamics plus C-terminal chromatin-reader domains, refining the catalytic mechanism.

    Evidence NMR, X-ray crystallography, mutagenesis, and kinetic methyltransferase assays with recombinant nucleosomes and H3K36A substrate mutants

    PMID:26002201 PMID:26292256

    Open questions at the time
    • Physiological activator of autoinhibition still unidentified
    • C-terminal domain contributions to chromatin targeting not structurally resolved
  6. 2015 High

    Defined ASH1L as a regulator of adult stem cell quiescence and self-renewal acting in genetic parallel with MLL1.

    Evidence Conditional knockout mice, bone marrow transplantation, cell-cycle analysis, and Ash1l/Mll1 double-mutant epistasis

    PMID:25866973

    Open questions at the time
    • Direct target genes mediating quiescence beyond Hox/Cdkn1b not fully mapped
    • Catalytic dependence of HSC phenotype not isolated
  7. 2016 High

    Identified LEDGF as a reader of ASH1L-deposited H3K36me2 that bridges to MLL complex recruitment, defining how this mark sustains MLL-dependent leukemia.

    Evidence Reciprocal ChIP-seq co-localization, Co-IP, leukemia transformation assays, and KDM2A antagonism

    PMID:27154821

    Open questions at the time
    • Whether ASH1L catalytic activity (vs scaffolding) drives transformation not resolved here
    • Direct ASH1L–LEDGF vs mark-mediated recruitment not distinguished
  8. 2016 Medium

    Extended ASH1L function to activity-dependent neuronal gene regulation, showing it can mediate transcriptional repression via promoter H3K36me2.

    Evidence Promoter pulldown, ChIP, Ash1l-knockout mice, and electrophysiological stimulation of cortical neurons

    PMID:27229316

    Open questions at the time
    • Mechanism by which H3K36me2 represses nrxn1α not defined
    • Single-locus focus limits generality
  9. 2017 High

    Revealed a chromatin-priming role in DNA repair, with DDB2-recruited ASH1L methylating H3K4 to enable XPC handoff in global-genome NER.

    Evidence Co-IP, ChIP, siRNA knockdown, UV survival, CPD excision assays, and co-localization imaging

    PMID:29109511

    Open questions at the time
    • H3K4 (vs H3K36) specificity at lesions contrasts with bulk biochemistry
    • Direct vs indirect ASH1L–XPC interplay not fully separated
  10. 2017 High

    Showed ASH1L directly activates Smad3 transcription via promoter H3K4me3 to drive Treg polarization, with a lncRNA/HDAC1 axis competing for promoter access.

    Evidence ChIP, knockdown, Co-IP at the Smad3 promoter, lnc-Smad3/HDAC1 interaction assays, and in vitro Treg polarization

    PMID:28598443

    Open questions at the time
    • How TGF-β signaling spatially coordinates ASH1L recruitment unresolved
    • Generalizability beyond Smad3 locus untested
  11. 2018 High

    Confirmed ASH1L as a Polycomb-counteracting activator in differentiation by enabling myoblast fusion and mesenchymal lineage decisions through SET-dependent promoter activation.

    Evidence RNA-seq, ChIP-seq, multi-system loss-of-function, SET-domain fragment overexpression/rescue, and in vivo transplantation

    PMID:30270478 PMID:30487570

    Open questions at the time
    • Recruitment to lineage-specific promoters not mechanistically defined
    • Direct vs secondary effects on differentiation factors not fully separated
  12. 2019 High

    Solved how ASH1L is physiologically activated, showing MRG15 binds an FxLP motif N-terminal to the SET domain to relieve post-SET autoinhibition.

    Evidence Independent crystal structures of ASH1L–MRG15 from two groups with methyltransferase assays and mutagenesis

    PMID:30827841 PMID:30827843

    Open questions at the time
    • Whether MRG15 acts allosterically or as a substrate adapter left ambiguous
    • In vivo requirement of MRG15 for ASH1L targeting not established here
  13. 2021 High

    Established that ASH1L catalytic activity is required for MLL-rearranged leukemia and that its autoinhibitory loop is a druggable pocket.

    Evidence Catalytic-dead vs WT rescue in conditional knockout leukemia models with ChIP-seq; fragment-based discovery of AS-99 with inhibitor co-crystal structures and in vivo efficacy

    PMID:33990599 PMID:34692539

    Open questions at the time
    • Selectivity of AS-99 against other K36 methyltransferases not detailed here
    • Scaffolding-independent catalytic requirement at all target genes not exhaustively mapped
  14. 2021 High

    Linked ASH1L to neurodevelopmental disease by showing its H3K4me3 deposition at synaptic genes maintains excitatory/inhibitory balance.

    Evidence Viral shRNA knockdown in prefrontal cortex, H3K4me3 ChIP-seq, patch-clamp electrophysiology, chemogenetic and pharmacological rescue

    PMID:34782621

    Open questions at the time
    • Direct ASH1L promoter binding vs indirect effects not separated for all synaptic genes
    • Relationship to its H3K36me2 activity in neurons unclear
  15. 2022 High

    Defined the ASH1L PHD finger as a reader of methylated H3K4 and uncovered a haploinsufficiency mechanism for autism via Polycomb-mediated EphA7 silencing.

    Evidence NMR structure and binding assays of the PHD finger; conditional knockout, H3K27me3 ChIP at EphA7, and ephrin-A5 rescue with behavioral readouts

    PMID:35081333 PMID:36033518

    Open questions at the time
    • How PHD H3K4me reading is coupled to catalysis not yet integrated
    • Direct vs indirect control of EZH2 activity at EphA7 unresolved
  16. 2023 High

    Resolved the role of MRG15 as a substrate-recruiting adapter via its chromodomain and extended the ASH1L–MRG15 module to FACT recruitment in NER.

    Evidence Co-IP, ChIP-seq, NER assays, XPC imaging, and in vitro methyltransferase assays comparing full-length MRG15 vs MRG domain alone

    PMID:37393406 PMID:37527654

    Open questions at the time
    • Reconciliation of adapter vs allosteric models across studies incomplete
    • In vivo stoichiometry of the ASH1L–MRG15–FACT module unknown
  17. 2023 Medium

    Placed ASH1L downstream of m6A regulation, showing METTL3/YTHDC2 stabilize ASH1L mRNA to dampen pathogenic Th17 responses.

    Evidence Overexpression/knockdown of METTL3, YTHDC2 and ASH1L, m6A mRNA stability assays, Th17 flow cytometry, and an in vivo EAU model

    PMID:36753389

    Open questions at the time
    • No structural/enzymatic validation of ASH1L action on IL-17/IL-23R
    • Direct ASH1L target promoters in Th17 not identified
  18. 2024 High

    Defined the integrated C-terminal reader module (PHD-BAH-bromodomain) and its DNA/H3K4me binding, revealing PHD–H3K4me3-dependent inhibition of catalysis as intramolecular cross-regulation.

    Evidence Crystal structure, in vitro binding and nucleosome assays, domain-mutant methyltransferase assays, ITC, and ChIP-seq in ESCs and cancer cells

    PMID:39034728 PMID:40044670

    Open questions at the time
    • How reader-mediated feedback is regulated in vivo unknown
    • Conflicting H3K4 methyl-state preferences across PHD vs PHD-BAH constructs
  19. 2024 High

    Quantified ASH1L's restricted, hierarchical contribution to H3K36me2 at developmental regulatory elements and nominated PBX2 as a recruitment factor.

    Evidence Sequential CRISPR knockouts of K36 methyltransferases in mesenchymal stem cells with ChIP-seq, transcriptomics, and motif analysis

    PMID:39390582

    Open questions at the time
    • Direct PBX2–ASH1L interaction not biochemically validated
    • Mechanism setting the NSD>ASH1L hierarchy unexplained
  20. 2024 Medium

    Extended ASH1L H3K4me3 promoter activation to additional disease-relevant programs and uncovered a non-catalytic DNA-protective function against UV damage.

    Evidence Osteoclast- and hepatocyte/HSC-specific conditional knockouts with ChIP at Stac2/CCL2/CSF1 promoters and AS-99 treatment; DNA damage mapping plus molecular dynamics of an AT hook in ASH1L-deficient cells

    PMID:38431690 PMID:38884271 PMID:39377228

    Open questions at the time
    • AT-hook-mediated CPD prevention is a single-lab novel mechanism awaiting independent confirmation
    • Catalytic vs structural contributions to the protective role not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ASH1L's locus-specific recruitment, the catalytic switch between H3K36me2 and context-dependent H3K4 methylation, and reader-mediated feedback are integrated into a unified targeting logic in vivo remains unresolved.
  • No unifying model reconciling H3K36me2 vs H3K4 methylation outputs across contexts
  • Sequence-specific recruitment factors largely unvalidated biochemically
  • In vivo interplay of autoinhibition, MRG15 activation, and PHD feedback not measured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0042393 histone binding 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140110 transcription regulator activity 3 GO:0003677 DNA binding 2
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-73894 DNA Repair 2
Partners
DDB2FACTLEDGFMRG15XPC
Complex memberships
ASH1L-MRG15 complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Human ASH1L (huASH1) protein localizes to both intranuclear speckles and intercellular tight junctions, as determined by immunostaining with multiple anti-huASH1 antibodies and double-immunofluorescence co-labeling with tight junction marker proteins in cultured cells. The protein contains a SET domain, PHD finger, four AT hooks, and a bromodomain-homology region. Immunofluorescence, double-immunofluorescence co-labeling with junctional markers, molecular cloning Proceedings of the National Academy of Sciences of the United States of America Medium 10860993
2007 Mammalian ASH1L associates with the transcribed region of active genes genome-wide, and its SET domain methylates histone H3K4 in vitro. Knockdown of ASH1L reduced H3K4 trimethylation at HoxA10 in vivo. Prior methylation at H3K9 reduced ASH1L-mediated H3K4 methylation. ASH1L and MLL1 display similar chromatin distributions but are recruited independently of each other (shown in MLL null cell lines). ChIP, in vitro methyltransferase assay, siRNA knockdown with ChIP, MLL null cell lines Molecular and cellular biology High 17923682
2011 Crystal structure of the human ASH1L catalytic domain reveals that the substrate binding pocket is blocked by a loop from the post-SET domain (autoinhibitory loop). Mutagenesis of this loop stimulates ASH1L histone methyltransferase activity. ASH1L specifically methylates histone H3 Lys-36 in vitro. X-ray crystallography, site-directed mutagenesis, in vitro methyltransferase assay The Journal of biological chemistry High 21239497
2013 Ash1l enhances expression of the deubiquitinase A20 (Tnfaip3) through H3K4 methylation at the Tnfaip3 promoter via its SET domain activity. A20 then facilitates deubiquitination of NF-κB signaling components NEMO and TRAF6, suppressing NF-κB and MAPK pathways and reducing IL-6 production in TLR-triggered macrophages. siRNA knockdown, ChIP, in vitro methyltransferase assay, SET domain mutant rescue, immunoprecipitation Immunity High 24012418
2013 Mammalian Ash1l methylates histone H3 Lys36 (H3K36 di- and trimethylation) independently of transcriptional elongation to counteract Polycomb silencing at Hox gene loci in embryonic stem cells. Treatment with P-TEFb inhibitor DRB (which blocks elongation) showed that Ash1l-dependent H3K36 methylation and exclusion of Polycomb group proteins occur in the absence of ongoing transcription. Genetics (Ash1l knockout mouse ES cells), DRB treatment, ChIP-seq, genome-wide H3K36me analysis PLoS genetics High 24244179
2015 Two loops in the ASH1L SET domain undergo concerted conformational dynamics critical for enzymatic activity: the autoinhibitory loop (post-SET) and a second loop in the SET-I subdomain. Point mutations in either loop substantially decrease ASH1L enzymatic activity. Three C-terminal chromatin-interacting domains greatly enhance ASH1L enzymatic activity, and ASH1L requires native nucleosome substrate for robust activity. NMR, X-ray crystallography, site-directed mutagenesis, in vitro methyltransferase assay Biochemistry High 26292256
2015 In vitro kinetic characterization shows ASH1L mono- and dimethylates H3K36 using recombinant nucleosome as substrate, requires native nucleosome (not histone peptides), and is inactive toward H3K4. The post-SET basic extension is critical for ASH1L (but not SETD2) activity. A H3K36A mutation in nucleosome substrate abolishes ASH1L activity. Radioactivity-based enzyme assays, western blotting, molecular modeling, nucleosome substrate with H3K36A mutation Biochimica et biophysica acta High 26002201
2015 Ash1l controls quiescence and self-renewal in adult hematopoietic stem cells (HSCs). Ash1l-deficient HSCs show markedly decreased quiescence, reduced Cdkn1b/1c expression, and fail to establish long-term trilineage hematopoiesis after transplantation. Ash1l also maintains expression of multiple Hox genes in hematopoietic progenitors. Combined loss of Ash1l and Mll1, but not either alone, induces overt hematopoietic failure (genetic epistasis). Conditional knockout mouse, bone marrow transplantation, cell cycle analysis, gene expression analysis, double-mutant epistasis The Journal of clinical investigation High 25866973
2016 ASH1L-written H3K36me2 chromatin mark is preferentially bound in vivo by LEDGF. ASH1L facilitates recruitment of LEDGF and wild-type MLL proteins to chromatin at key leukemia target genes. The H3K36me2 demethylase KDM2A antagonizes MLL-associated leukemogenesis. ASH1L is required for MLL-dependent transcription and leukemic transformation. ChIP-seq, Co-IP, genome-wide co-localization analysis, leukemia transformation assays, KDM2A genetic/pharmacological antagonism Cancer discovery High 27154821
2016 Ash1l mediates activity-dependent transcriptional repression of neurexin-1α (nrxn1α) in neurons. Neuronal firing (50 Hz, 10 min) triggers binding of Ash1l to the nrxn1α promoter and enrichment of H3K36me2 at the promoter region. Ash1l knockout completely abolished activity-dependent repression of nrxn1α. Zinc finger protein pulldown of promoter-bound proteins, ChIP, Ash1l knockout mice, primary cortical neuron electrophysiological stimulation Scientific reports Medium 27229316
2017 ASH1L is recruited by DDB2 to UV-damaged chromatin, where it methylates H3K4 at nucleosomes containing cyclobutane pyrimidine dimers (CPDs). This H3K4me facilitates docking of XPC to nucleosomal histone octamers for handoff in global-genome NER. In ASH1L-depleted cells, XPC chromatin binding is impaired, CPD excision is suppressed, and UV hypersensitivity results. DDB2, ASH1L, and XPC transiently co-localize on H3K4-methylated nucleosomes after UV. Co-IP, ChIP, siRNA knockdown, UV survival assay, CPD excision assay, co-localization by immunofluorescence Nature communications High 29109511
2017 Ash1l facilitates TGF-β-induced regulatory T cell (Treg) polarization by directly targeting the Smad3 promoter to increase H3K4 trimethylation and upregulate Smad3 expression. The lncRNA lnc-Smad3 competes with Ash1l by recruiting HDAC1 to silence Smad3 transcription; TGF-β-activated Smad3 suppresses lnc-Smad3, recovering promoter accessibility to Ash1l. ChIP, siRNA/shRNA knockdown, co-IP (Ash1l with Smad3 promoter), lnc-Smad3/HDAC1 interaction assay, in vitro Treg polarization Nature communications High 28598443
2018 Ash1L promotes myoblast fusion (MF) by activating expression of the key MF gene Cdon. Ash1L is required to counteract Polycomb repressive activity at selected myogenesis genes. Loss of Ash1L in vivo, ex vivo, and in vitro impairs myoblast fusion. RNA-seq, ChIP-seq, in vivo/ex vivo/in vitro loss-of-function (siRNA, knockout), rescue experiments Nature communications High 30487570
2018 Ash1l controls fate decisions of mesenchymal progenitor cells. Silencing Ash1l hampers osteogenesis and chondrogenesis while promoting adipogenesis. Overexpression of an Ash1l SET domain-containing fragment promotes osteogenic/chondrogenic differentiation. The function requires histone methyltransferase activity, as a SET-domain fragment (but not ΔN mutant lacking SET) was active. Ash1l increases H3K4me3 at promoters of osteogenic/chondrogenic transcription factors. siRNA knockdown, overexpression of SET domain fragments, ChIP (H3K4me3 at target promoters), in vitro differentiation assays, subcutaneous transplantation Stem cells (Dayton, Ohio) Medium 30270478
2019 Crystal structure of ASH1L SET domain in complex with MRG15 reveals that MRG15 binds via its MRG domain to an FxLP motif in ASH1L N-terminal to the SET domain. This binding displaces the autoinhibitory (AI) loop from the post-SET domain, opening the substrate-binding pocket and activating ASH1L H3K36me2 catalytic activity. X-ray crystallography, in vitro methyltransferase assay, site-directed mutagenesis Structure (London, England : 1993) High 30827841 30827843
2019 Crystal structure of ASH1L tandem MRG15-interacting and SET domains in complex with MRG15 shows that ASH1L-MRG15 interaction principally occurs via a segment N-terminal to the SET domain. Mrg15 binding destabilizes the autoinhibitory loop in the post-SET region without direct contact, by inducing subtle structural changes in the SAM binding pocket (conformational coupling between SAM and substrate binding sites). X-ray crystallography, in vitro methyltransferase assay Structure (London, England : 1993) High 30827843
2021 ASH1L knockdown in mouse prefrontal cortex (PFC) reduces H3K4me3 at promoters of ASD/epilepsy-related synaptic genes, diminishes GABAergic inhibition, enhances glutamatergic transmission, and increases PFC pyramidal neuronal excitability, causing seizures and early mortality. Chemogenetic inhibition of PFC pyramidal neurons combined with diazepam rescues synaptic imbalance and seizures. Viral shRNA knockdown in PFC, ChIP-seq (H3K4me3), whole-cell patch clamp electrophysiology, chemogenetics (DREADD), behavioral/EEG seizure monitoring Nature communications High 34782621
2021 Fragment-based screening identified first-in-class small molecule inhibitors (lead compound AS-99) that bind to the autoinhibitory loop region in the ASH1L SET domain, as confirmed by crystal structures of ASH1L-inhibitor complexes. AS-99 blocks MLL leukemia cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces leukemia burden in vivo. Fragment-based screening, medicinal chemistry, X-ray crystallography of inhibitor complexes, cell proliferation/apoptosis assays, in vivo leukemia mouse models Nature communications High 33990599
2021 ASH1L catalytic activity (H3K36me2) is required for promotion of MLL-AF9-induced leukemic transformation. Wild-type but not catalytic-dead ASH1L rescues leukemia maintenance in ASH1L-deleted cells. ASH1L directly binds promoters of MLL-AF9 target genes and modifies local H3K36me2 levels. Conditional knockout mouse model, retroviral rescue with WT vs. catalytic-dead ASH1L mutant, ChIP-seq, in vitro and in vivo leukemia models Frontiers in oncology High 34692539
2022 Ash1l haploinsufficiency causes autistic-like behaviors linked to excessive synapses due to synapse pruning deficits. Mechanistically, deletion of Ash1l in neurons leads to downregulation of EphA7 through accumulation of EZH2-mediated H3K27me3 in the EphA7 gene body. Supplying ephrin-A5 (EphA7 ligand) in Ash1l+/- mice restores synapse pruning and rescues discrimination deficits. Conditional knockout mouse, ChIP (H3K27me3 at EphA7), ephrin-A5 rescue experiment, synapse quantification, behavioral assays Neuron High 35081333
2022 The ASH1L PHD finger non-selectively binds all three methylation states of H3K4 (me1, me2, me3) with comparable affinities. NMR structure of the PHD finger bound to H3K4me2 peptide shows a narrow binding groove restricting interaction with the dimethyl-ammonium moiety. The ASH1L PHD finger is identified as a native reader of methylated H3K4. NMR structure determination, peptide binding assays (ITC/NMR), site-directed mutagenesis Frontiers in oncology High 36033518
2023 The ASH1L-MRG15 complex deposits H3K4me3 genome-wide (outside active gene promoters) after UV irradiation, priming chromatin for XPC relocations. ASH1L-MRG15 also recruits the histone chaperone FACT to DNA lesions. Without ASH1L, MRG15 or FACT, XPC is misplaced and cannot deliver lesions to TFIIH for verification. Full-length MRG15 (but not MRG domain alone) enhances ASH1L activity by recruiting nucleosome substrate via MRG15 chromodomain. Co-IP, ChIP-seq, siRNA knockdown, NER activity assays, XPC relocalization imaging, in vitro methyltransferase assay Nature communications High 37393406
2023 Full-length MRG15 (but not the MRG domain alone) enhances ASH1L catalytic activity by recruiting ASH1L to nucleosome substrate via the MRG15 chromodomain. MRG15 binding does not alter the conformation of the ASH1L SET domain autoinhibitory loop or the SAM cofactor binding site in solution, suggesting MRG15 functions as a substrate-recruiting adapter rather than an allosteric activator. In vitro methyltransferase assay, NMR, nucleosome binding assays, MRG domain vs full-length MRG15 comparison, small molecule inhibitor potency assay Structure (London, England : 1993) High 37527654
2023 METTL3 promotes ASH1L expression post-transcriptionally by enhancing ASH1L mRNA stability in a YTHDC2-dependent m6A reader mechanism. Elevated ASH1L in turn decreases IL-17 and IL-23R expression, reducing pathogenic Th17 responses. Overexpression/knockdown of METTL3, YTHDC2, and ASH1L; m6A mRNA stability assays; flow cytometry for Th17; in vivo EAU model FASEB journal Medium 36753389
2024 Crystal structure and functional analysis of the ASH1L C-terminal region (bromodomain, PHD finger, and BAH domain) shows: ASH1LPHD recognizes H3K4me2/3; ASH1LBD and ASH1LBAH have DNA-binding activities; the ASH1LBAH domain's DNA-binding drives association with linker DNA in nucleosomes; the PHD-BAH interface stabilizes the BAH fold merging two domains into one module; and interaction of ASH1LPHD with H3K4me3 is inhibitory to the H3K36me2 catalytic activity of ASH1L. Crystal structure, in vitro binding assays, nucleosome interaction assays, methyltransferase activity assays with domain mutants, ChIP-seq in ESCs Nature communications High 40044670
2024 ASH1L mediates H3K4me3 modification at the Stac2 promoter in osteoclast progenitors, increasing Stac2 transcription. STAC2 then protects against RANKL-initiated inflammation during osteoclast formation. Conditional deletion of Ash1l in osteoclast progenitors results in osteoporosis and enhanced osteoclastogenesis in vivo. Conditional knockout mouse (osteoclast progenitor-specific), ChIP (H3K4me3 at Stac2 promoter), osteoclast differentiation assay, bone histomorphometry Cell death and differentiation Medium 38431690
2024 Systematic perturbation of H3K36 methyltransferases demonstrates that ASH1L's H3K36me2 activity is restricted to regulatory elements of developmentally relevant genes. PBX2 is implicated as a potential ASH1L recruitment factor at these sites. ASH1L activity is positioned at the bottom of a hierarchy: NSD1 > NSD2 > NSD3 > ASH1L for H3K36me1/2 deposition. Sequential CRISPR knockouts of K36MTs in mouse mesenchymal stem cells, ChIP-seq, transcriptomics, motif analysis Genome biology High 39390582
2024 ASH1L guards enhancer and promoter sequences against UV-induced cyclobutane pyrimidine dimer (CPD) formation at C-containing dinucleotides (but not TT dinucleotides or 6-4 photoproducts). This protective function is associated with H3K4me3 and H3K27ac histone marks that interact with ASH1L PHD and BRD motifs, respectively. Molecular dynamics simulations identified an AT hook in ASH1L that alters DNA geometry to disfavor pyrimidine dimerization. DNA damage mapping in ASH1L-proficient vs. deficient cells, molecular dynamics simulation, ChIP data correlation, mutation frequency analysis in skin cancers Nucleic acids research Medium 38884271
2024 ASH1L-mediated H3K4me3 modification increases CCL2 and CSF1 expression in hepatocytes and hepatic stellate cells, recruiting and polarizing M2-like pro-tumorigenic macrophages that enhance tumor proliferation and suppress CD8+ T cell activation in HCC. Conditional Ash1l deletion in hepatocytes or HSCs mitigates fibrosis and HCC development. Conditional knockout mice (Ash1lflox/flox Alb-Cre and GFAP-CreERT2), ChIP (H3K4me3 at CCL2/CSF1 promoters), single-cell RNA-seq, multicolor flow cytometry, AS-99 inhibitor treatment Advanced science Medium 39377228
2024 The PHD-BAH domain of ASH1L preferentially binds H3K4me2 peptide over H3K4me1 and H3K4me3 in pull-down and ITC assays. The W2603A mutation in the PHD-BAH domain disrupts interaction with H3K4me2 in vitro. Deletion of the PHD-BAH domain in cholangiocarcinoma cells increases apoptosis and reduces proliferation, with dysregulation of the PSMB family gene set. Prokaryotic fusion protein pull-down, ITC, site-directed mutagenesis, CRISPR-Cas9 domain deletion, cell proliferation/apoptosis assays Anti-cancer agents in medicinal chemistry Medium 39034728

Source papers

Stage 0 corpus · 73 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Mammalian ASH1L is a histone methyltransferase that occupies the transcribed region of active genes. Molecular and cellular biology 177 17923682
2013 Histone methyltransferase Ash1l suppresses interleukin-6 production and inflammatory autoimmune diseases by inducing the ubiquitin-editing enzyme A20. Immunity 137 24012418
2016 ASH1L Links Histone H3 Lysine 36 Dimethylation to MLL Leukemia. Cancer discovery 133 27154821
2011 Crystal structure of the human histone methyltransferase ASH1L catalytic domain and its implications for the regulatory mechanism. The Journal of biological chemistry 112 21239497
2000 huASH1 protein, a putative transcription factor encoded by a human homologue of the Drosophila ash1 gene, localizes to both nuclei and cell-cell tight junctions. Proceedings of the National Academy of Sciences of the United States of America 92 10860993
2013 Ash1l methylates Lys36 of histone H3 independently of transcriptional elongation to counteract polycomb silencing. PLoS genetics 76 24244179
2017 Ash1l and lnc-Smad3 coordinate Smad3 locus accessibility to modulate iTreg polarization and T cell autoimmunity. Nature communications 62 28598443
2018 Epigenetic Control of Mesenchymal Stem Cell Fate Decision via Histone Methyltransferase Ash1l. Stem cells (Dayton, Ohio) 60 30270478
2015 Ash1l controls quiescence and self-renewal potential in hematopoietic stem cells. The Journal of clinical investigation 58 25866973
2021 Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures. Nature communications 54 34782621
2019 Mutations in ASH1L confer susceptibility to Tourette syndrome. Molecular psychiatry 53 31673123
2015 miR-142-3p down-regulation contributes to thyroid follicular tumorigenesis by targeting ASH1L and MLL1. The Journal of clinical endocrinology and metabolism 53 25238203
2015 Kinetic characterization of human histone H3 lysine 36 methyltransferases, ASH1L and SETD2. Biochimica et biophysica acta 42 26002201
2022 ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph receptor gene to autism spectrum disorder. Neuron 41 35081333
2021 Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity. Nature communications 38 33990599
2020 Novel role of ASH1L histone methyltransferase in anaplastic thyroid carcinoma. The Journal of biological chemistry 37 32398261
2019 Structural Insights into Stimulation of Ash1L's H3K36 Methyltransferase Activity through Mrg15 Binding. Structure (London, England : 1993) 32 30827843
2017 Novel MCA/ID syndrome with ASH1L mutation. American journal of medical genetics. Part A 31 28394464
2016 Histone methyltransferase Ash1L mediates activity-dependent repression of neurexin-1α. Scientific reports 29 27229316
2021 Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like behaviors. Communications biology 28 34145365
2017 The Histone Methyltransferase Ash1l is Required for Epidermal Homeostasis in Mice. Scientific reports 27 28374742
2015 Two Loops Undergoing Concerted Dynamics Regulate the Activity of the ASH1L Histone Methyltransferase. Biochemistry 27 26292256
2015 Reprogramming of Polycomb-Mediated Gene Silencing in Embryonic Stem Cells by the miR-290 Family and the Methyltransferase Ash1l. Stem cell reports 27 26549848
2023 METTL3 inhibits autoreactive Th17 cell responses in experimental autoimmune uveitis via stabilizing ASH1L mRNA. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25 36753389
2017 ASH1L histone methyltransferase regulates the handoff between damage recognition factors in global-genome nucleotide excision repair. Nature communications 25 29109511
2023 Exosomes from hypoxia-pretreated adipose-derived stem cells attenuate ultraviolet light-induced skin injury via delivery of circ-Ash1l. Photodermatology, photoimmunology & photomedicine 23 36582030
2019 Structural Basis of MRG15-Mediated Activation of the ASH1L Histone Methyltransferase by Releasing an Autoinhibitory Loop. Structure (London, England : 1993) 23 30827841
2024 ASH1L in Hepatoma Cells and Hepatic Stellate Cells Promotes Fibrosis-Associated Hepatocellular Carcinoma by Modulating Tumor-Associated Macrophages. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 22 39377228
2023 The ASH1L-AS1-ASH1L axis controls NME1-mediated activation of the RAS signaling in gastric cancer. Oncogene 22 37805663
2020 Role of Ash1l in Tourette syndrome and other neurodevelopmental disorders. Developmental neurobiology 19 33258273
2018 The Trithorax protein Ash1L promotes myoblast fusion by activating Cdon expression. Nature communications 18 30487570
2024 Systematic perturbations of SETD2, NSD1, NSD2, NSD3, and ASH1L reveal their distinct contributions to H3K36 methylation. Genome biology 15 39390582
2023 Novel NUP98::ASH1L Gene Fusion in Acute Myeloid Leukemia Detected by Optical Genome Mapping. Cancers 14 37296904
2021 Vorinostat, a histone deacetylase inhibitor, ameliorates the sociability and cognitive memory in an Ash1L-deletion-induced ASD/ID mouse model. Neuroscience letters 14 34509565
2021 Histone H3K36me2-Specific Methyltransferase ASH1L Promotes MLL-AF9-Induced Leukemogenesis. Frontiers in oncology 14 34692539
2023 ASH1L-MRG15 methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair. Nature communications 13 37393406
2022 Structural insight into ASH1L PHD finger recognizing methylated histone H3K4 and promoting cell growth in prostate cancer. Frontiers in oncology 13 36033518
2021 ASH1L mutation caused seizures and intellectual disability in twin sisters. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 13 34373061
2016 ASH1L Suppresses Matrix Metalloproteinase through Mitogen-activated Protein Kinase Signaling Pathway in Pulpitis. Journal of endodontics 13 28041684
2020 A chromosome 1q22 microdeletion including ASH1L is associated with intellectual disability in a Chinese family. Molecular cytogenetics 10 32518592
2024 Expansion of the Genotypic and Phenotypic Spectrum of ASH1L-Related Syndromic Neurodevelopmental Disorder. Genes 9 38674358
2020 Knockdown of ASH1L methyltransferase induced apoptosis inhibiting proliferation and H3K36 methylation in bovine cumulus cells. Theriogenology 9 33296745
2024 The histone methyltransferase ASH1L protects against bone loss by inhibiting osteoclastogenesis. Cell death and differentiation 8 38431690
2023 Ash1L ameliorates psoriasis via limiting neuronal activity-dependent release of miR-let-7b. British journal of pharmacology 8 37766518
2022 The methyltransferase enzymes KMT2D, SETD1B, and ASH1L are key mediators of both metabolic and epigenetic changes during cellular senescence. Molecular biology of the cell 8 35196069
2019 Unleashing the Power of ASH1L Methyltransferase. Structure (London, England : 1993) 8 31067442
2016 ASH1L (a histone methyltransferase protein) is a novel candidate globin gene regulator revealed by genetic study of an English family with beta-thalassaemia unlinked to the beta-globin locus. British journal of haematology 8 27434206
2025 Non-canonical activation of MAPK signaling by the lncRNA ASH1L-AS1-encoded microprotein APPLE through inhibition of PP1/PP2A-mediated ERK1/2 dephosphorylation in hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR 7 40646641
2022 ASH1L contributes to oocyte apoptosis by regulating DNA damage. American journal of physiology. Cell physiology 6 36094439
2025 Ash1l loss-of-function results in structural birth defects and altered cortical development. Brain : a journal of neurology 5 38943682
2023 MRG15 activates histone methyltransferase activity of ASH1L by recruiting it to the nucleosomes. Structure (London, England : 1993) 5 37527654
2023 Hypoxia-sensitive cells trigger NK cell activation via the KLF4-ASH1L-ICAM-1 axis, contributing to impairment in the rat epididymis. Cell reports 5 37952156
2022 Neural Hyperactivity Is a Core Pathophysiological Change Induced by Deletion of a High Autism Risk Gene Ash1L in the Mouse Brain. Frontiers in behavioral neuroscience 4 35449559
2025 Has_circ_ASH1L acts as a sponge for miR-1254 to promote the malignant progression of cervical cancer by targeting CD36. Cancer gene therapy 3 39748122
2025 Novel heterozygous ASH1L nonsense variant involved in mild intellectual disability. Frontiers in neurology 3 39902220
2025 Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation. Nature communications 3 40044670
2023 Systematic perturbations of SETD2, NSD1, NSD2, NSD3 and ASH1L reveals their distinct contributions to H3K36 methylation. bioRxiv : the preprint server for biology 3 37905045
2025 Loss-of-function mutations of microRNA-142-3p promote ASH1L expression to induce immune evasion and hepatocellular carcinoma progression. World journal of gastroenterology 2 39777247
2025 CircSHOC2 regulates steroid hormone synthesis in ovarian granulosa cells through the mir-130b-5p/ASH1L pathway. Zoological research 2 41017397
2024 ASH1L guards cis-regulatory elements against cyclobutane pyrimidine dimer induction. Nucleic acids research 2 38884271
2024 Structure-Based Development of Novel Spiro-Piperidine ASH1L Inhibitors. Journal of medicinal chemistry 2 39680643
2024 Abnormal H3K4 enzyme catalytic activity and neuronal morphology caused by ASH1L mutations in individuals with Tourette syndrome. European child & adolescent psychiatry 1 38634863
2024 PHD-BAH Domain in ASH1L Could Recognize H3K4 Methylation and Regulate the Malignant Behavior of Cholangiocarcinoma. Anti-cancer agents in medicinal chemistry 1 39034728
2024 Gonadal Mosaicism for an ASH1L Intragenic Deletion Makes a Bridge Between MRD52 and 1q22 Microdeletion. American journal of medical genetics. Part A 1 39655631
2024 Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model. Genes 1 39766886
2023 A Saudi Girl With Co-occurring CHD1 (Pilarowski-Bjornsson Syndrome) and ASH1L Gene Variants. Cureus 1 38174187
2026 The Emerging Role of Histone Methyltransferase ASH1L in Tumor Development. Anti-cancer agents in medicinal chemistry 0 42083345
2026 CDK4 Mediates Cisplatin Resistance in Renal Cell Carcinoma (RCC) Cells by Regulating the ASH1L-CTR1 Axis. Oncology research 0 42220427
2025 Comprehensive multi-omics analysis of histone acetylation modulators identifies ASH1L as a novel aggressive marker for osteosarcoma. Discover oncology 0 40504347
2025 [Evolution of DEE-SWAS into photosensitive epilepsy in a patient with an ASH1L gene mutation]. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova 0 41283842
2025 A novel de novo missense variant in ASH1L associated with mild autism spectrum disorder and an uneven cognitive profile: a case report. Journal of medical case reports 0 41291913
2025 Revealing the impact of partial gene duplications in ASH1L: integration of optical genome mapping and RNA sequencing. Molecular cytogenetics 0 41327308
2024 Dynamic Regulation OF The Chromatin Environment By Ash1L Modulates Human Neuronal Structure And Function. bioRxiv : the preprint server for biology 0 39677608

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