5-Hydroxymethylcytocine-Mediated Epigenetic Regulation in Autism Spectrum Disorders
Basic & Clinical
Autism spectrum disorders (ASD) includes an array of disorders including Autism, Rett syndrome and Fragile X syndrome. Accumulating evidence suggests a complex etiology for ASD that may include epigenetic and environmental factors. Epigenetics refer to inheritable changes not induced by DNA sequence alteration including DNA methylation, histone modification and non-coding RNA. DNA methylation has been proposed to play a role in autism. This hypothesis is supported by the discovery of the abnormal expression of MeCP2 in autism brain. In traditional concept, four different nucleotides exist in the genome: A, G, C, and T. Epigenetic studies have demonstrated that nucleotide C could be methylated (mC). Very recently, a novel DNA base 5-hydroxymethylcytosine (5-hmC) was discovered in mammalian brain and it constitutes a significant portion of nucleotides in the brain cells. These findings suggest 5-hmC modification might also be an important epigenetic modification. Hydroxylation of 5-mC to 5-hydroxymethylcytosine (5-hmC) presents a particularly intriguing epigenetic regulatory paradigm in mammalian brain, where its dynamic regulation is critical. The research team has established the technology to profile the genome-wide distribution of 5-hmC. Preliminary studies indicate that this particular DNA modification is widespread and could play significant roles in neurodevelopment. Given the neurodevelopmental phenotypes associated with ASD, it is important to evaluate its contribution to ASD pathogenesis. This Pilot project will investigate the potential involvement of 5-hmC in autism spectrum disorders. These studies will generate a large amount of data and could be shared with other investigators, and could contribute to the identification of autism genetic/epigenetic risk factors. This research will determine the role of 5-hydroxymethylcytosine-mediated epigenetic modulation in ASD. Two specific aims will be tested: Aim 1. To determine the genome-wide 5-hmC distribution profiles using multiple mouse models of Rett syndrome and human patients; Aim 2. To determine the genome-wide 5-hmC distribution profiles in both autistic and normal brains.