Wednesday, April 2, 2025
4/2/2025
Epigenetic mechanisms of histone methyltransferase ASH1L in autism spectrum disorder - Project Abstract ASH1L (Absent, Small, or Homeotic discs 1-Like) is a histone methyltransferase facilitating gene expression through its-mediated chromatin modification. Recent genetic studies on large cohorts of autism spectrum disorder (ASD) patients identify ASH1L is one of top ASD risk genes. The genetic findings are further supported by many clinical reports that children diagnosed with ASD acquire various de novo ASH1L mutations. To understand the pathogenic role of disruptive ASH1L mutations in ASD pathogenesis, we used the Ash1l conditional knockout (cKO) mice to show that deletion of Ash1l in the mouse brain was sufficient to cause autistic- like behaviors and cognitive memory deficits, suggesting that disruptive ASH1L mutations are likely to be causally involved in ASD genesis. Our following studies showed that Ash1l-KO mice developed general neural hyperactivity, suggesting that loss of ASH1L causes excitation/inhibition (E/I) imbalance of neural signals in the brain. Furthermore, our recent study reported that postnatal administration of SAHA, a histone deacetylase inhibitor, ameliorated core autistic-like behaviors and cognitive memory of Ash1l-deficient mice, suggesting that histone acetylation and ASH1L-mediated histone modification have a synergistic function in maintaining normal brain functions. Building upon these discoveries at the molecular, brain, and organismal levels, we propose that ASH1L facilitates gene expression through its-mediated histone modification in the brain. Loss of ASH1L impairs the expression of genes critical for maintaining E/I balance in the brain, which consequently leads to neural hyperactivity and behavioral deficits in Ash1l-KO mice. To further investigate the epigenetic mechanisms of ASH1L in ASD pathogenesis, we will used the Ash1l-cKO mice to examine the function, transcriptome, and epigenome of cortical excitatory neurons, inhibitory neurons, and astrocytes in the brain. Specifically, we will (1) dissect the functional roles of three neural lineages in contributing to the neural hyperactivity and behavioral deficits in Ash1l-KO mice; (2) examine lineage-specific transcriptome dynamics to identify genes involved in the functional abnormalities of the Ash1l-deficient brain; (3) examine lineage-specific epigenome dynamics to identify ASH1L-mediated epigenetic mechanisms involved in the functional abnormalities of the Ash1l-deficient brain. Completion of this study will not only significantly advance our understanding of the ASH1L-mediated epigenetic mechanisms in regulating gene expression in the brain and their pathogenic roles in ASD genesis, but also potentially lead to the development of new therapeutic approaches to treat the ASH1L-mutation-induced neurodevelopmental diseases.
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