Cytosine methylation is 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) a-KG-dependent hydroxylation gives a new perspective on the previously observed plasticity in 5mC-dependent regulatory processes. We have explored the roles of Tet-mediated epigenetic modulation in gene regulation, genomic stability, and tumorigenesis.
In recent years, increasing evidence indicates that multiple neurodevelopmental, neurodegenerative, and psychiatric disorders are caused, in part, by aberrant epigenetic modifications. We have examined the dynamic DNA modifications during neurodevelopment and aging and their roles in the pathogenesis of human diseases. Using the technology that we developed, we generated the first genome-wide maps of 5hmC during brain development, providing a detailed epigenomic view of regulated 5hmC in the CNS. Our analyses suggest that 5hmC-mediated epigenetic regulation may broadly impact brain development, and its dysregulation could contribute to autism. Besides autism, our recent works have also linked 5hmC and Tet proteins to multiple neurological disorders, including fragile X-related disorders, ischemic brain injury, and Alzheimer’s diseases.
Furthermore, recent studies suggest that post-transcriptional mRNA modifications are dynamically regulated and have functions beyond fine-tuning the structure and function of RNA. These dynamic RNA modifications represent a critical new realm for gene regulation in the form of “Epitranscriptomics,” a new field expanding at a rapid pace. We are exploring the role of different RNA modifications in regulating neural development and neuronal functions.