Mutations in chromatin regulators underlie many neurodevelopmental disorders. The importance of chromatin regulators may relate to a unique challenge that neurons face among cell types: neurons must maintain genome integrity without cell division for an organism’s full life span while simultaneously allowing enough genome plasticity for learning and memory. We are studying how neuron-specific chromatin features enable neuronal function and how mutations in chromatin regulators lead to neurological disease.

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For example, we study the specific types of DNA methylation found in neurons. In most differentiated cell types, DNA methylation occurs primarily in the CG sequence, but during postnatal brain development neurons accumulate high levels of DNA methylation in the CA sequence, as well as hydroxymethylation in the CG sequence. Mutations in the known writers, readers, and erasers of these modifications are implicated in neurodevelopmental disorders and cancer, but the function of these modifications is not fully understood. We are investigating why these specific types of DNA methylation accumulate in neurons, how they regulate transcription and genome integrity, and how mutations in regulators of DNA methylation lead to neurodevelopmental disorders and cancer.

One regulator of DNA methylation we study is MeCP2, a neuronally-enriched protein that binds to methylated DNA in both the CG and CA sequence. Mutations in MeCP2 cause the neurodevelopmental disorder Rett syndrome. The function of MeCP2 has puzzled researchers for years because the severe disease symptoms that result from its mutation are accompanied by only subtle changes in gene expression. To investigate the function of MeCP2, we have developed a mouse line in which the MeCP2 protein can be rapidly degraded in the brain. We are using this system to distinguish the immediate molecular consequences of acute MeCP2 loss from the secondary consequences of long-term neurological impairment. These experiments will enable better understanding of MeCP2 and DNA methylation in the brain, and this approach can be broadly applied to other chromatin regulators implicated in neurological disease.