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Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures

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  • Luye Qin

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Jamal B. Williams

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Tao Tan

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Tiaotiao Liu

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Qing Cao

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Kaijie Ma

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

  • Zhen Yan

    (State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences)

Abstract

ASH1L, a histone methyltransferase, is identified as a top-ranking risk factor for autism spectrum disorder (ASD), however, little is known about the biological mechanisms underlying the link of ASH1L haploinsufficiency to ASD. Here we show that ASH1L expression and H3K4me3 level are significantly decreased in the prefrontal cortex (PFC) of postmortem tissues from ASD patients. Knockdown of Ash1L in PFC of juvenile mice induces the downregulation of risk genes associated with ASD, intellectual disability (ID) and epilepsy. These downregulated genes are enriched in excitatory and inhibitory synaptic function and have decreased H3K4me3 occupancy at their promoters. Furthermore, Ash1L deficiency in PFC causes the diminished GABAergic inhibition, enhanced glutamatergic transmission, and elevated PFC pyramidal neuronal excitability, which is associated with severe seizures and early mortality. Chemogenetic inhibition of PFC pyramidal neuronal activity, combined with the administration of GABA enhancer diazepam, rescues PFC synaptic imbalance and seizures, but not autistic social deficits or anxiety-like behaviors. These results have revealed the critical role of ASH1L in regulating synaptic gene expression and seizures, which provides insights into treatment strategies for ASH1L-associated brain diseases.

Suggested Citation

  • Luye Qin & Jamal B. Williams & Tao Tan & Tiaotiao Liu & Qing Cao & Kaijie Ma & Zhen Yan, 2021. "Deficiency of autism risk factor ASH1L in prefrontal cortex induces epigenetic aberrations and seizures," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26972-8
    DOI: 10.1038/s41467-021-26972-8
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