This video describes the following:

  • In which chromosome is ASH1L located?

  • What are the protein domains in ASH1L?

  • What is the structure of ASH1L?

  • What is the function of ASH1L?

  • How does a mutation in ASH1L disrupt its function?


SPECIAL CREDIT NOTE: This video has been designed and compiled by Dr. Sofia Lizarraga and members of her laboratory at University of South Carolina. Care4ASH1L is very grateful to their contribution & would like to thank Dr. Sofia Lizarraga, Janay Vacharasin and Anna Bagnell for contributing to this video

Copyright © 2020 by Dr. Sofia Lizarraga & Care4ASH1L. All rights reserved.


ASH1L & Genomics

ASH1L & H3K36

ASH1L & Cancer

ASH1L & Autism

Summary on ASH1L

ASH1L & Genomics

  • Autism spectrum disorder (ASD) affects 1 in 59 children and represents a growing public health concern worldwide. Between 50 to 75% of ASD cases are of unknown or complex genetic etiology.

  • In particular, de novo truncating and missense mutations in ASH1L have been identified in large autism cohorts.

  • Furthermore, recent evidence suggests that ASH1L is associated with severe forms of autism, as patients with mutations in ASH1L suffer from intellectual disabilities, speech difficulties, seizures and postnatal microcephaly (failure of the brain to grow postnatally).

  • Therefore, the human phenotypes associated with mutations in ASH1L suggest a major role for this chromatin modifier during the development of neuronal connectivity.

ASH1L & H3K36

  • ASH1L methylates Histone H3 on Lysine 36, which is proposed to result primarily in transcriptional activation.

  • Histone methylation is mainly attached to the basic side chains of lysine and arginine residues. Various histone lysine methylations impart either the activating or repressive effect on gene transcription, which depends on the site, degree of methylation, genomic location, and the status of other coexisting PTMs.

  • In general, methylations of histone H3 at lysine 4, 36 and 79 (H3K4, H3K36 and H3K79) are linked to the transcriptionally active state, whereas methylations of histone H3 at lysine 9 and 27 (H3K9, H3K27) and histone H4 at lysine 20 (H4K20) are associated with gene silencing.

  • In addition to gene transcription regulation, histone lysine methylations are also found involved in numerous other cellular events including DNA damage repair, DNA replication, and mRNA splicing.

The Role of ASH1L in Cancer

  • ASH1L (absent, small, or homeotic-like 1) is a histone lysine methyltransferase that catalyzes mono- and dimethylation of histone H3 lysine 36.

  • Previous studies discussed that ASH1L is implicated in a variety of cancers. ASH1L is an H3K36 methyltransferase implicated in cancers and autism disorders.

  • ASH1L is a trithorax group histone lysine methyltransferase, which is involved in gene activation.  It is a large, ~3000 amino acid protein containing multiple functional domains that include the SET domain and three chromatin-interacting domains (bromodomain, PHD domain and bromo-associated homology (BAH) domain) at the C-terminus.

  • Emerging data link ASH1L to the development of malignant solid tumors.  Genetic alternations of ASH1L have been identified in gastrointestinal cancer, kidney cancer, liver cancer, breast cancer, thyroid cancer, bladder cancer and prostate cancer. ASH1L regulates expression of HOX genes and is involved in leukemogenesis.

The Role of ASH1L in AUTISM

  • ASH1 like histone lysine methyltransferase (ASH1L) was identified as a major risk factor for autism.

  • ASH1L, as a histone lysine methyltransferase, is highly expressed in both embryonic and adult human brains.  It plays an important role in neuronal development and has been identified as a risk gene for autism spectrum disorders (ASDs) and other developmental disorders. 

  • ASH1L is involved in epigenetic regulation of neuronal activity. ASH1L regulates nrxn1α, which is one of the neurexins essential for synapse formation. Mutants of nrxn1α are widely observed in neurological diseases, including schizophrenia and ASD. ASH1L binds to the promoter of nrxn1α in neurons and enriched this region with H3K36me2, resulting in long-term repression of nrxn1α transcription. Therefore, dysregulation of ASH1L could likely result in aberrant neuronal activity.

  • Other studies show that mutations of ASH1L exist in ASD patient samples.  These mutations are clustered around annotated domains of ASH1L, and patients with ASH1L disruptive variation showed symptoms of intellectual disability (ID) and ASD. Patients that carry de novo ASH1L loss-of-function variant exhibit various neurodevelopmental disorders. These results firmly demonstrate the necessity to further investigate the roles of ASH1L in neurological diseases.


  • ASH1L regulates the expression of various genes involved in leukemia, neuronal activity, and muscle growth and repair. Hence the involvement of ASH1L in global gene expression still needs extensive investigation

  • It would be important to identify genes that are sensitive to ASH1L inhibition and to identify novel ASH1L target genes and assess the H3K36 levels of these genes upon treatment of ASH1L inhibitors.



Simons Searchlight ASH1L

Simons Searchlight is an initiative of the Simons Foundation Autism Research Initiative (SFARI) that aims to better understand genetic neurodevelopmental conditions, specifically those associated with autism spectrum disorder (ASD).

Currently, Simons Searchlight collects family, medical, developmental and behavioral information through online surveys and phone interviews with families and individuals. Biospecimen collection is performed either remotely or at in-person family meetings.Today, 159 genes and 19 CNVs are part of the Simons Searchlight community.

Click here to learn more on the Simons Searchlight ASH1L. 

In order to understand more about Simons Searchlight, please visit their official website