Chromatin regulation in neural development, autistic disorders, and cancer.
Epigenetic regulation plays important roles in stem cell differentiation, tissue development and tumorigenesis. We are interested in the function of chromatin regulation of signaling pathways important for neural development, brain tumor growth and autism pathogenesis. In addition to the traditional genetic, molecular and biochemical methods, we are employing advanced proteomic and genomic approaches to improve our understanding of the transcriptional regulation of these developmental important and cancer-related signaling pathways at the chromatin level. Our studies are mainly focused on two areas.
Epigenetic regulation of the Sonic Hedgehog (Shh) signaling pathway in neural development and in medulloblastoma growth.
Shh signaling plays important morphogenic and mitogenic roles during development and adult homeostasis. Mutations that result in dysregulated Shh signaling lead to developmental diseases and are associated with a growing number of cancers. Recently we have identified a dynamic epigenetic network including chromatin remodeling factors and histone modification enzymes that play essential role in regulating Shh signaling transcription outcomes. Using a mouse model of Shh-type medulloblastoma, we are investigating the epigenetic mechanisms regulating medulloblastoma gene expression and growth. We are also exploring the possibility of inhibiting tumor initiation and progression by modulating the epigenetic regulators involved in Shh signaling.
Function of chromatin remodeling complexes in neuronal activity-dependent transcription and synapse plasticity.
The prototypical SWI/SNF-like chromatin remodeling BAF complexes, which regulate gene expression by modulating chromatin structures, have been linked to autism spectrum disorders. Mutations in genes encoding several BAF subunits cause diseases with autistic symptoms and the core subunit Brg1/Smarca4 was predicted to be a key player in the autism gene network. Recently, we have deleted Brg1 specifically in neurons and discovered that Brg1 is required for synapse development and MEF2-mediated activity-induced gene expression and synapse plasticity. We are investigating how chromatin remodeling factors are recruited to specific target gene sites and how they response to neuronal calcium signaling to activate gene expression during synapse development and maturation. These studies will shed light to mechanism of chromatin regulation in neural development and in autism pathogenesis.