Exploring disruption of DNA methylation in autism spectrum disorders

  • Awarded: 2017
  • Award Type: Pilot
  • Award #: 508034

Advances in genetics have defined a large number of high-confidence risk genes that are mutated in autism spectrum disorder (ASD). Many of these ASD genes encode epigenetic modifiers that regulate gene expression in the developing brain. However, how mutation of these genes leads to ASD is not well understood.

Harrison Gabel and his colleagues at Washington University in St. Louis are exploring how disruption of one epigenetic mechanism, DNA methylation, can contribute to ASD. Building on recent genetic studies that have identified ASD-associated mutations in the DNMT3A DNA methyltransferase, they will establish a mouse model of DNMT3A disruption in ASD. They will characterize the alterations in DNA methylation, gene expression and neuronal cell function that occur in the brains of these mice and examine how these disruptions can contribute to ASD-relevant behaviors.

Based on recent observations that DNMT3A deposits a unique form of non-CG DNA methylation across the genome of neurons during development, these studies will test the hypothesis that DNMT3A mutations alter this brain-specific non-CG methylation to drive neural dysfunction. In parallel studies, Gabel and colleagues will characterize the molecular effects of specific DNMT3A missense mutations that have been identified in individuals with ASD. Through the analysis of these mutations in a neuronal cell culture system in vitro and the generation of mice carrying precise disease-associated mutations in vivo, Gabel’s team will determine which aspects of DNMT3A function are inactivated across all ASD-associated DNMT3A mutations. These planned experiments will isolate the core disruption of DNMT3A that must occur to drive ASD pathology.

Taken together, these studies will provide new models for the study of the molecular etiology of ASD caused by mutations in DNMT3A. In addition, this work will begin to define convergent etiology that is shared between autism and related neurodevelopmental disorders.

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