Understanding epigenetic contributions to autism

  • Awarded: 2022
  • Award Type: Targeted: Genomics of ASD: Pathways to Genetic Therapies
  • Award #: 1013053

Among the highly penetrant risk genes for autism spectrum disorder (ASD), many of them encode synaptic proteins and chromatin regulators. Given the importance of synaptic function to the developing brain, it is not surprising that variants in synaptic genes are linked to ASD. However, the broad functionality of chromatin regulators and their pervasive expression pattern across multiple cell and tissue types raise an outstanding question of how dysfunction of chromatin regulators contributes to the etiology of ASD.

While studying the epigenetic regulation of neuronal gene expression in the brain, the lab of Zhaolan (Joe) Zhou uncovered a previously unappreciated group of genes harboring broad enhancer-like chromatin domains (BELD). These BELD features are conserved from rodents to humans, enriched in genes involved in synaptic function and appear postnatally concomitant with the peak of synaptogenesis. Consistent with previous genetic findings, BELD genes, such as NRXN1, are highly implicated in neurodevelopmental disorders, particularly ASD, and their expression is preferentially downregulated in individuals with idiopathic autism1.

These findings have raised a hypothesis that the transcription of BELD genes is particularly sensitive to alterations in ASD-associated chromatin regulators. Thus, while other cell types and tissues can tolerate the loss of one copy of chromatin genes, BELD genes in the brain may be preferentially altered, leading to impaired synaptic functions relevant to the manifestation of autism. Given that copy number variations (CNVs) in the NRXN1 gene are among the most frequently observed single-gene variants in ASD and different alleles of Nrxn1 show distinct contributions to ASD-relevant behavioral phenotypes in mice2, we plan to use different alleles of Nrxn1 as a model to assess the developmental formation and biological significance of BELD features.

The goal is to advance our understanding of the epigenetic contribution to autism, the molecular and cellular consequences of ASD-related genetic risks, and to provide a foundation to identify possible points of biological convergence and promote mechanism-based therapeutic development.


  1. Zhao Y.-T. et al. Genome Res. 28, 933-942 (2018) PubMed
  2. Xu B. et al. PLoS Genet. 19, e1010659 (2023) PubMed
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