PROJECT SUMMARY/ABSTRACT Autism spectrum disorders (ASD) comprises a group of complex and heterogeneous neurodevelopmental diseases that range in severity of shared traits including social, behavioral, and language impairments. Mounting evidence indicate that fewer than 10% of patients with ASD harbor rare structural DNA variations and mutations with strong penetrance, suggesting that environmental and epigenetic factors contribute to most cases by disrupting critical neurogenic processes during brain development. Indeed, prior studies have observed unusual brain growth in early life of patients with ASD, a phenotype that complements neuropathological evidence of defects in neurogenesis, migration, synaptogenesis, and proliferation. Normal neurodevelopment entails coordinated spatiotemporal regulation of gene expression/pre-mRNA splicing and epigenetic modifications, particularly of genes involved in neurogenesis, migration, and neuronal function. An important region of the brain enriched for neural progenitors that contribute to neurogenesis, growth, and hodology is the subventricular zone (SVZ) of the lateral ventricle. On examining this neurogenic region for epigenetic changes between autistic and typically developing individuals, our preliminary data indicated that aberrant DNA methylation (an epigenetic mechanism) at an alternatively spliced exon of a gene previously implicated in autism by DNA sequence mutations, MeCP2, associates with splicing defects of the gene in an ASD individual without such mutations. Alterations to DNA methylation and other chromatin modifications in ASD appear to be widespread. Together, these results implicate epigenetic dysregulation of the SVZ in contributing to the neuropathological and heterogeneous phenotypic expression of ASD. However, the consequence of and extent to which epigenetic dysregulation may contribute to ASD remain largely unexplored. We seek to fill this very important gap in knowledge. Based on our promising preliminary data, we hypothesize that alterations to the chromatin landscape, in particular intragenic DNA methylation states, over neurodevelopmental genes contribute to transcriptomic changes via aberrant pre-mRNA splicing events underlying ASD. To address this hypothesis, we will take advantage of our unique collection of postmortem SVZ tissue from idiopathic autism-diagnosed and age-matched typically developing males, and aim to determine the extent of alterations to (1) the epigenome (i.e. genome-wide DNA methylation and histone modification states) and (2) the RNA transcriptome in ASD. Integrating these datasets will provide novel insight into the mechanism(s) by which neurodevelopmental genes may be dysregulated in ASD and reveal potentially useful therapeutic targets for the disorders. Additionally, this study will likely broaden the field of ASD research to elucidate an epigenetic etiology, which may also capture and account for previously unexplored environmental risk factors and the heterogeneous phenotypic expression of ASD.

R21MH114005

2017-09-01

2019-08-31