ASH1L

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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/c

...

ASH1L

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.

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)

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ASH1L

ASH1L

ASH1L

Overview

Gene Structure and Expression

Protein Function and Mechanism

Role in Neurodegeneration

Alzheimer's Disease

Neurodevelopmental Disorders

Common Variants and Risk Alleles

Therapeutic Implications

See Also

External Links

References