Chromatin Regulation in Brain Development and Disease

Division Of Basic Sciences - Nci

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Abstract

During FY2025, we made significant progress on this research project studying chromatin and epigenetics in brain development and how mutations in chromatin regulators lead to neurodevelopmental disorders and cancer. In one part of the research project, we are using molecular and genomic approaches to understand the function of a neuron-enriched form of DNA methylation, mCA. mCA is methylated by DNMT3A, which is mutated or overexpressed in neurodevelopmental disorders and cancer, but little is known about why DNMT3A methylates CA DNA in neurons but not in other cell types, or how mCA influences protein binding in neurons. During FY2025, we made significant progress understanding why mCA accumulates in neurons and identifying proteins that bind methylated or unmethylated CA DNA. These experiments are providing insight into the function of mCA and how changes in mCA caused by DNMT3A mutations lead to neurodevelopmental disorders and cancer. A second part of this research project is focused on the methyl-DNA-binding protein MeCP2, the only protein currently known to bind mCA DNA. Loss-of-function mutations in MeCP2 cause the neurodevelopmental disorder Rett syndrome, and MeCP2 is overexpressed in multiple cancers. To investigate the function of MeCP2, we developed an approach to rapidly degrade the MeCP2 protein in neurons, and we are using this approach to distinguish the primary and secondary consequences of MeCP2 loss. During FY2025, we made significant progress identifying the primary effects of rapid MeCP2 degradation on gene expression, epigenetic modifications, and DNA damage. These experiments are providing insight into the primary functions of MeCP2 and how disrupting these functions leads to Rett syndrome and cancer.