Autism spectrum disorder ASD) is one of the most common pervasive developmental disorders and public concern is elevating. Emerging evidence supports ASD as a disorder with strong genetic components. Linkage and candidate-gene analyses, genome-wide association studies and assessments of chromosomal variations have uncovered a wide range of genes with predisposing mutations and polymorphisms associated with ASD. Mounting evidence supports the view that epigenetic mechanisms modulate many critical neural functions via regulation of gene expression. Dysregulation of epigenetic processes can have long-lasting effects on the development and functional integrity of neural circuitry. The recent identification of activity-dependent DNA demethylation in mammalian neurons offers an exciting entry point to address the scope and function of dynamic epigenetic regulation of gene expression and synaptic plasticity and its contribution to neural processes in normal and pathological conditions. The neuronal activity-induced gene, Gadd45b, also plays important roles in active DNA demethylation, has been shown to be differentially expressed in the post-mortem tissue of ASD patients, and therefore provides us with an entry point to study the role and mechanisms of epigenetic contributions to neurodevelopmental disorders. ASD is a group of developmental disabilities characterized by impairments in social interaction and communication and restricted and restricted interest and stereotyped behaviors. Therefore, characterization of the behavioral phenotype in gain- and loss- function of Gadd45b mice will help to understand the role of Gadd45b in ASD. I also propose to perform RNA-seq and whole genome bisulfite sequencing on Gadd45b KO and WT neurons to investigate the role of Gadd45b in regulating gene expression and DNA methylation changes. Data generated in this study will be made available to the scientific community studying neurodevelopmental disorders such as ASD. Completion of these experiments should generate empirically testable hypotheses of the function of Gadd45b target genes and have a potential to identify novel ASD related genes. I believe this gene is a viable candidate to investigate the interaction of genetic context, developmental pathology and disease risk. I expect that these studies of Gadd45b will reveal how a single gene may be responsible for rendering cells more vulnerable to pathogenesis and thus contribute to cumulative risk impact in psychiatric disorders.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
