Regulation and reversibility of DNA methylation changes associated with autism spectrum disorders
- Awarded: 2021
- Award Type: Bridge to Independence
- Award #: 663662
Accumulating evidence indicates that autism spectrum disorder (ASD) susceptibility mutations are frequently found within genes encoding chromatin regulators that control the expression of genes across the genome. Notably, mutations in genes encoding both ‘writers’ and ‘readers’ of cytosine methylation, a key epigenetic modification involved in gene regulation, are associated with ASD. Furthermore, DNA methylation patterns are significantly altered in postmortem brain samples from individuals with ASD1, consistent with a more general role for methylation misregulation in ASD etiology.
Interventions to address DNA methylation changes could therefore be an attractive potential therapeutic strategy for ASD. However, the regulatory mechanisms controlling neuronal DNA methylation patterns and the reversibility of ASD-associated behavioral phenotypes caused by methylation dysregulation remain poorly understood.
In the current project, Hume Stroud plans to assess regulatory mechanisms of DNA cystine methyltransferase DNMT3A, a high-confidence ASD risk gene, as well as downstream effects on the neuronal methylome. He also plans to examine whether subsequent re-expression of DNMT3A can reverse cellular and behavioral phenotypes in a DNMT3A mouse model and whether there is a specific developmental window in which such rescue is possible.
Findings from these studies will advance our understanding of the function of cytosine methylation in neurons. They will also provide critical therapeutic insights into whether DNMT3A function can be restored, and if so, whether children would likely need to be treated early in life or whether adults may also benefit from such an approach.
- Critical windows and reversibility of autism associated with mutations in chromatin remodelers
- Exploring disruption of DNA methylation in autism spectrum disorders
- Neuronal activity-dependent chromatin remodeling in autism
- Understanding how ASD-risk mutations in the chromatin regulators Pogz and Suv420h1 affect cortical development
- Regulation of autism risk genes by m6A methylation