Autism is comprised of a clinically heterogeneous group of disorders, collectively termed autism spectrum disorders (ASD), which share common features of impaired social relationship, impaired language and communication, and limited range of interests and behavior. Although monogenic disorders collectively only account for a minority of autism cases (10-15%), the molecular alterations in these disorders could reveal common pathogenic pathways shared by ASDs. 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) alpha-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. To unravel the biology of 5hmC, we have developed approaches to map genome-wide 5hmC distribution. Using these technologies, we generated genome-wide maps of 5hmC during brain development, providing a detailed epigenomic view of regulated 5hmC in CNS. Our analyses suggest a highly dynamic regulation of 5hmC during neurodevelopment. More specifically, we have identified both stable and dynamic DhMRs (Differential 5-hydroxymethylated regions) during neurodevelopment. Surprisingly DhMRs are highly enriched in the genes that have been implicated in autism. We have also found that the loss of Mecp2 leads to the specific reduction of 5hmC signals at dynamic DhMRs of cerebellum. More intriguingly, we have recently found that the loss of Fmr1, responsible for fragile X syndrome, could alter the 5hmC signals at dynamic DhMRs in mice as well. These data suggest that 5hmC-mediated epigenetic regulation may broadly impact brain development, and its dysregulation could contribute to autism. In this proposal, we will determine whether there is consistent alteration of 5hmC modification at dynamic DhMRs among mouse models of ASD-linked monogenic disorders, and determine the functional role(s) of Tet-mediated epigenetic modulation in ASD-linked monogenic disorders.
Several disorders caused by single-gene mutations, such as Fragile X syndrome and Rett syndrome, are associated with autism, reflecting a greatly increased risk of autism conferred by the mutations. Although these monogenic disorders collectively only account for a minority of autism cases (10-15%), the molecular alterations in these disorders could reveal common pathogenic pathways shared by autism. In this proposed study, we will investigate whether 5hmC and Tet-mediated epigenetic modulation could contribute to the molecular pathogenesis of autism-linked monogenic disorders.
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