Regulation and function of DNMT3A-mediated methylation in the brain.

The DNA methyltransferase DNMT3A is mutated in individuals with neurological disorders such as autism and intellectual disabilities. DNMT3A is highly expressed in the nervous system, primarily methylating atypical non- CG sequences, particularly at CA sites (mCA). The mCA mark is partially bound by MECP2, a protein mutated in Rett syndrome, which causes severe cognitive impairments. Deletions of either DNMT3A or MECP2 in the brain lead to significant gene expression defects and severe neurological and behavioral issues in mice. Despite the importance of mCA in brain function, its regulatory mechanisms and precise roles are largely unknown. Our lab has identified a novel phosphorylation site within the methyltransferase domain of DNMT3A that is responsible for adding methylation to the DNA. Preliminary data suggests that blocking this phosphorylation site in mice eliminates mCA in the brain without affecting DNMT3A protein stability. Unlike DNMT3A deletion mice, which die neonatally, the phospho-defective mice survive into adulthood but develop progressive behavioral issues. The exact mechanisms by which the phosphorylation site affects mCA, gene regulation, and animal behavior remain unclear. The proposed experiments aim to (1) elucidate the role of phosphorylation on DNMT3A function, (2) define the role of mCA in neural gene regulation, and (3) examine how neuronal activity influences DNMT3A phosphorylation and DNMT3A-mediated mCA. These insights could lead to new therapeutic strategies for neurological disorders such as autism spectrum disorders. Project Number: 5R01MH142292-02 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Hume Akahori Stroud | Institution: UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX | Award Amount: $548,446 | Activity Code: R01 | Study Section: Molecular Neurogenetics Study Section[MNG] View on NIH RePORTER: https://reporter.nih.gov/project-details/11400403