The role of H3K36 methyltransferases on non-CpG methylation patterning in the mammalian brain

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Project Summary: Human genetic studies have linked autism and related neurodevelopmental disorders (NDD) to disruption of genes encoding epigenetic factors. While mutations in these genes can affect more than one pathway that leads to ASD, identification of a common molecular pathway across genetic causes of ASD can provide insight into broadly applicable therapies. Recent evidence from our laboratory suggests that a neuronal-specific form of DNA methylation is a shared epigenetic modification that is disrupted in ASD-associated neurodevelopmental disease. Though DNA methylation is classically considered to only occur in mammalian cells in the CpG context, neurons are uniquely enriched for methylation in non-CpG contexts established by DNMT3A. This non-CpG methylation primarily occurs at CA dinucleotides (mCA) and is critical for proper neuronal development and function. Though mCA plays an important role in regulating neuronal gene expression, it is not known how the mCA landscape is faithfully established across the neuronal genome, and whether additional NDDs involve disruption of mCA. Recent studies outside the nervous system have suggested that histone modifications may play a central role in directing DNMT3A-mediated DNA methylation across the genome, but it is not known to how these histone modifications influence DNMT3A and mCA throughout the neuronal genome. Intriguingly, mutations in H3K36 histone methyltransferases have been recently identified in ASD gene studies. Additionally, recent studies conducted outside the nervous system have suggested that H3K36 methylation recruits DNMT3A and regulates its activity. In this proposal, I will determine how disruption of H3K36 methylation-mediated interactions with DNMT3A disturbs critical patterns of mCA across the neuronal genome to drive brain dysfunction. In Aim 1, I will disrupt NDD-relevant H3K36 methyltransferases and measure how DNMT3A recruitment and mCA are affected. This will define the mechanisms underlying histone and DNA modification dynamics on regulating neuronal transcription and building our basic understanding of how disruption of mCA drives disease. In Aim 2, I will explore how loss of H3K36 dimethylase NSD1 causes dysregulation of neuronal genes via shared neuronal chromatin pathology observed across heterogenous clinical syndromes of ASD. I will use genomic approaches to examine how altered DNA methylation as a result of NSD1 loss affects enhancer activity to drive transcriptional dysregulation in nervous system dysfunction and disease. This analysis will begin to identify key downstream chromatin associated factors across a common molecular pathway involved in multiple genetic causes of ASD to provide insight into functional cellular outcomes and broadly applicable therapies.