Reading and writing DNA methylation in the mammalian brain
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Graduate group
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Genetics and Genomics
Subject
DNMT3A
MeCP2
Rett syndrome
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Abstract
DNA methylation is a chemical modification of cytosine nucleotides essential for the regulation of genome function in mammals. Although its roles in embryonic development and cellular differentiation have been well-studied, far less is known about how DNA methylation regulates brain function, despite the fact that mutations in the DNA methylation machinery lead to profound neurologic dysfunction in humans. Here, we explored the roles of DNA methylation in postmitotic neurons of the brain by selectively disrupting both the predominant “writer” (DNMT3A) and “reader” (MeCP2) of DNA methylation in mice. We found that loss of DNMT3A-catalyzed DNA methylation leads to broad changes in gene expression, influencing MeCP2 occupancy across the genome as well as impacting the activity of both the Polycomb repressive complex and COMPASS family member proteins. Additionally, we characterized the molecular consequences of a loss-of-function mutation in MeCP2 that leads to Rett syndrome, a progressive neurodevelopmental disorder. We found that MeCP2 dysfunction results in gradual accumulation of subtle transcriptional changes across postnatal life, preferentially affecting highly-methylated genes with minimal chromatin signatures of Polycomb repression. Taken together, our results provide insights into the multifaceted roles of de novo DNA methylation in brain function, suggesting that DNA methylation works in tandem with histone modifications to maintain precise gene expression in neurons across postnatal life. These findings expand our knowledge of the pathogenesis of neurological disorders involving impaired readout of DNA methylation in the brain.