[R01] Regulation and function of DNMT3A-mediated methylation in the brain.
Ente: National Institute of Mental Health
Scadenza: 2030-05-31
Importo max: 548.446 EUR
Paese: US
Descrizione
Project Summary:
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.
Istituzione: UT SOUTHWESTERN MEDICAL CENTER
PI: Hume Akahori Stroud
Progetto: 5R01MH142292-02
Settori: National Institute of Mental Health
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