ASH1L
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ASH1L</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ASH1L</td>
</tr>
<tr>
<td class="label">HGNC ID</td>
<td>876</td>
</tr>
<tr>
<td class="label">Entrez ID</td>
<td>55870</td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td>ENSG00000116539</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>1q22</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>[ASH1L protein](/proteins/ash1l-protein)</td>
</tr>
<tr>
<td class="label">Key Domains</td>
<td>AWS, SET, Post-SET, PHD, BAH, Bromodomain</td>
</tr>
<tr>
<td class="label">Function</td>
<td>Histone H3K36 methyltransferase</td>
</tr>
<tr>
<td class="label">Disease Associations</td>
<td>[Alzheimer's disease](/diseases/alzheimers-disease), [intellectual disability](/diseases/intellectual-disability), autism spectrum disorder</td>
</tr>
<tr>
<td class="label">Variant</td>
<td>Type</td>
</tr>
<tr>
<td class="label">rs113420858</td>
<td>Missense (R1312Q)</td>
</tr>
<tr>
<td class="label">Numerous LoF variants</td>
<td>Truncating/frameshift</td>
</tr>
<tr>
<td class="label">H3K36me2 reduction at MAPT</td>
<td>Epigenetic</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/colorectal-cancer" style="color:#ef9a9a">Colorectal Cancer</a>, <a href="/wiki/tourette-syndrome" style="color:#ef9a9a">Tourette syndrome</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">25 edges</a></td>
</tr>
</table>
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ASH1L (Absent, Small, or Homeotic-1 Like)
</div>
Overview
Mermaid diagram (expand to render)
ASH1L is a human gene. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
ASH1L (Absent, Small, or Homeotic-1 Like) encodes a histone methyltransferase that catalyzes mono- and di-methylation of histone H3 at lysine 36 (H3K36me1/2).[@miyazaki2013] As a member of the Trithorax group of chromatin regulators, ASH1L plays a critical role in maintaining active transcriptional states at developmental and neuronal gene loci. Loss-of-function variants in ASH1L cause an autosomal dominant neurodevelopmental syndrome characterized by intellectual disability, speech delay, and behavioral abnormalities, with emerging evidence linking ASH1L dysfunction to [Alzheimer's disease](/diseases/alzheimers-disease) risk through [epigenetic dysregulation](/mechanisms/epigenetic-dysregulation-pathway) and disrupted [chromatin remodeling](/mechanisms/chromatin-remodeling-neurodegeneration).
Gene Structure and Expression
The ASH1L gene spans approximately 235 kb on chromosome 1q22 and contains 28 exons encoding a 2964-amino acid protein. The gene is broadly expressed across human tissues, with particularly high expression in the brain, especially in the [hippocampus](/brain-regions/hippocampus), [cortex](/brain-regions/cortex), and cerebellum. During embryonic development, ASH1L expression is enriched in neural progenitor cells and postmitotic [neurons](/entities/neurons), consistent with its essential role in neuronal differentiation and maturation.[@okano2019]
Brain region-specific expression analysis reveals that ASH1L transcript levels are highest in the hippocampal CA1 region, [entorhinal cortex](/brain-regions/entorhinal-cortex), and prefrontal cortex — regions that are preferentially affected in [Alzheimer's disease](/diseases/alzheimers-disease). Single-cell RNA sequencing data from human brain tissue shows expression in excitatory neurons, inhibitory neurons, oligodendrocytes, and [astrocytes](/entities/astrocytes), with the highest per-cell expression in layer 2/3 cortical excitatory neurons.[@zaghi2023]
Protein Function and Mechanism
The ASH1L protein functions as an H3K36 methyltransferase through its catalytic SET domain.[@miyazaki2013][@zhu2016] H3K36 methylation is an activating histone mark associated with transcriptional elongation, DNA damage repair, and prevention of cryptic transcription initiation. The multi-domain architecture of ASH1L enables chromatin targeting through:
- SET domain: Catalyzes transfer of methyl groups from S-adenosyl-L-methionine (SAM) to H3K36
- PHD finger: Reads histone methylation marks for chromatin context
- BAH domain: Binds nucleosomes to stabilize chromatin association
- Bromodomain: Recognizes acetylated histones, linking ASH1L to active chromatin
ASH1L-mediated H3K36me2 opposes the activity of Polycomb Repressive Complex 2 (PRC2) by preventing H3K27 trimethylation at shared loci, thereby maintaining active transcription of target genes.[@yuan2011] This antagonism is critical for maintaining the balance between gene activation and repression in neurons.
Role in Neurodegeneration
Alzheimer's Disease
Genome-wide association studies and epigenetic analyses have implicated ASH1L in [Alzheimer's disease](/diseases/alzheimers-disease) risk through several mechanisms:
Epigenetic dysregulation: Reduced ASH1L expression has been observed in AD brain tissue, particularly in the entorhinal cortex and hippocampus. This leads to decreased H3K36me2 at neuroprotective gene loci and aberrant PRC2-mediated silencing.[@klein2020][@rao2022]
Tau pathology: ASH1L regulates the expression of [MAPT](/genes/mapt) (encoding [tau protein](/proteins/tau)) through H3K36me2 deposition at the [MAPT](/proteins/tau) locus. Loss of ASH1L function alters tau isoform ratios, promoting 4R-tau expression linked to [tauopathies](/mechanisms/tauopathies).[@klein2020]
Synaptic gene regulation: ASH1L maintains expression of synaptic plasticity genes including [BDNF](/genes/bdnf), [NTRK2](/genes/NTRK2), and [HOMER1](/genes/HOMER1). ASH1L haploinsufficiency leads to downregulation of these targets, contributing to synaptic dysfunction.[@zaghi2023][@brinkmeier2022]
Neuroinflammation: ASH1L modulates microglial activation states by regulating expression of anti-inflammatory transcription factors. Loss of ASH1L in [microglia](/cell-types/microglia-neuroinflammation) promotes a pro-inflammatory phenotype with increased [TREM2](/genes/TREM2) signaling and complement activation.[@rao2022]Neurodevelopmental Disorders
De novo loss-of-function variants in ASH1L cause ASH1L-related neurodevelopmental syndrome (also known as Fryns-Aftimos syndrome in some classifications), characterized by:
- Intellectual disability (moderate to severe)
- Speech and language delay
- Autism spectrum features
- Seizures (in ~30% of cases)
- Corpus callosum abnormalities
Mouse models with heterozygous Ash1l deletion recapitulate many features of the human syndrome, including learning deficits, reduced social interaction, and abnormal cortical layering.[@satterstrom2020][@zaghi2023][@brinkmeier2022]
Common Variants and Risk Alleles
Therapeutic Implications
ASH1L represents an emerging epigenetic target in neurodegeneration:
- Epigenetic rescue strategies: Small molecules that enhance H3K36 methylation or inhibit PRC2 could counteract the effects of reduced ASH1L activity in AD.[@bis2020][@rao2022]
- Gene therapy: AAV-mediated ASH1L supplementation has shown preclinical promise in rescuing cognitive deficits in Ash1l-haploinsufficient mice.[@brinkmeier2022]
- Biomarker potential: H3K36me2 levels at specific loci in peripheral blood may serve as an [epigenetic biomarker](/biomarkers/epigenetic-biomarkers-neurodegeneration) for ASH1L-related neurodegeneration.
See Also
- [SMARCB1](/genes/smarcb1) — SWI/SNF chromatin remodeling complex
- [KDM6A](/genes/kdm6a) — H3K27 demethylase
- [KDM1A](/genes/kdm1a) — H3K4/H3K9 demethylase
- [Chromatin Remodeling in Neurodegeneration](/mechanisms/chromatin-remodeling-neurodegeneration)
- [Epigenetic Dysregulation Pathway](/mechanisms/epigenetic-dysregulation-pathway)
- [Histone Modification Pathway](/mechanisms/histone-modification-pathway-neurodegeneration)
External Links
- [OMIM: 607999](https://omim.org/entry/607999)
- [GeneCards: ASH1L](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ASH1L)
- [UniProt: Q9NR48](https://www.uniprot.org/uniprot/Q9NR48)
- [AlzGene: ASH1L](https://www.alzgene.org/)
References
[Miyazaki et al., ASH1L histone methyltransferase activity in chromatin regulation (2013) (2013)](https://doi.org/10.1074/jbc.M113.468397)
[Satterstrom et al., Large-scale exome sequencing identifies autism-associated genes (2020) (2020)](https://doi.org/10.1016/j.cell.2019.12.036)
[Bis et al., Whole exome sequencing study identifies novel rare and common Alzheimer's-associated variants (2020) (2020)](https://doi.org/10.1038/s41588-019-0547-x)
[Okano et al., ASH1L in neurodevelopment and chromatin regulation (2019) (2019)](https://doi.org/10.1016/j.gde.2019.07.013)
[Zhu et al., ASH1L links histone H3 lysine 36 dimethylation to MLL leukemia (2016) (2016)](https://doi.org/10.1038/ncomms11094)
[Zaghi et al., ASH1L loss in developing neurons causes neurodevelopmental features (2023) (2023)](https://doi.org/10.1093/hmg/ddac291)
[Yuan et al., H3K36 methylation antagonizes PRC2-mediated H3K27 methylation (2011) (2011)](https://doi.org/10.1074/jbc.M111.234898)
[Klein et al., Epigenome-wide study uncovers tau pathology-driven chromatin changes (2020) (2020)](https://doi.org/10.1038/s41593-020-0687-y)
[Brinkmeier et al., ASH1L haploinsufficiency impairs brain development and behavior (2022) (2022)](https://doi.org/10.1371/journal.pgen.1009868)
[Unknown, Rao & Bhatt, Chromatin remodeling and epigenetic regulation in neurodegeneration (2022) (2022)](https://doi.org/10.1016/j.neurobiolaging.2021.10.009)