Dynamic DNA Modifications in Brain and Diseases

Epigenetics is broadly defined as the heritable changes in gene expression and function that do not alter DNA sequence. As an intermediate regulatory paradigm between DNA sequences and gene expression, epigenetic mechanisms can exert substantial influence on brain development on a scale that we are only beginning to appreciate. Furthermore increasing evidence indicates that multiple neurodevelopmental, neurodegenerative, and psychiatric disorders are caused, at least in part, by aberrant epigenetic modifications. Cytosine methylation serves as a critical epigenetic mark by modifying DNA-protein interactions that influence transcriptional states and cellular identity. 5-methylcytosine (5mC) has generally been viewed as a stable covalent modification to DNA; however, the fact that 5-mC can be enzymatically modified to 5- hydroxymethylcytosine (5hmC) by Tet family proteins through Fe(II) α-KG-dependent hydroxylation gives a new perspective on the previously observed plasticity in 5mC-dependent regulatory processes. Epigenetic plasticity in DNA methylation-related regulatory processes influences activity-dependent gene regulation and learning and memory in the central nervous system (CNS). Hydroxylation of 5mC to 5hmC presents a particularly intriguing epigenetic regulatory paradigm in the mammalian brain, where its dynamic regulation is critical. Emerging evidence also suggests potential epigenetic roles for a novel DNA adenosine modification, N6- methyladenine (N6mA). Thus the discovery of both 5hmC/5fC/5caC and N6mA in mammalian genome significantly increases the DNA epigenetic complexity and intriguingly all these modifications are enriched in brain. The proposed works here will integrate various disciplines (genetics/genomics, bioinformatics, biochemistry, and cell biology) to understand the crosstalk among the dynamic DNA modifications during neurodevelopment and aging, and their roles in the pathogenesis of neurological disorders.