Epigenetic regulation plays important roles in stem cell differentiation, tissue development and tumorigenesis. Together with transcription factors, chromatin regulators determine the diverse but precise transcription outcomes in response to environmental signals. We are interested in the function of chromatin regulation of signaling pathways important for neural development. 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 during neural development and cancers. 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 reported that Brg1, a chromatin remodeling factor, plays a dual role in regulating Shh signaling: Brg1 both represses basal expression and activates Shh-induced target gene transcription. Our model suggests that a complex chromatin environment, including Gli transcription factors, Brg1 associated factors and additional histone modification enzymes, regulates precise Shh signaling output. Currently we are investigating 1) chromatin modifications regulating Shh target gene expression at the basal and Shh-induced conditions; 2) protein networks associated with Gli proteins and Brg1 determining the transcription outcomes of Shh target genes; 3) Shh/Gli target genes in different developing tissues. In addition, using a mouse Shh-dependent medulloblastoma model, we are examining 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. Activity-dependent transcription in neurons is critical for the proper function and development of the neural system including in long term potentiation, memory formation, synaptic plasticity, neuronal survival, neurogenesis, dendritic arborization, and wiring. We have found that neuron-specific chromatin remodeling BAF complexes regulate activity-dependent gene transcription and dendritic outgrowth. We plan to use a proteomics approach to identify changes of subunits/interacting proteins or their modifications in response to neuronal activation. The goal of this project is to reveal the signaling pathway from neuronal activities to chromatin remodeling and to determine the developmental and physiological roles of BAF complexes in neuronal morphology and synaptic functions.
Interested students are welcome to rotate in the lab.
Selected references
Wu, J.I. (2012) Diverse functions of ATP-dependent chromatin remodeling complexes in development and cancer. Acta Biochimica et Biophysica Sinica. 44, 54-69
Zhan, X., Shi, X., Zhang, Z., Chen, Y., Wu, J.I. (2011) Dual role of Brg chromatin remodeling factor in Shh signaling during neural development. Proc. Natl. Acad. Sci. USA, 108, 12758-12763. PMC315094
Zhan, X., and Wu, J. (2009) Epigenetics in embryonic and adult neurogenesis. Cell Science Review 6, 104-128
Ho L, Ronan JL, Wu J, Staahl BT, Chen L, Kuo A, Lessard J, Nesvizhskii AI, Ranish J, Crabtree GR. (2009) An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency. Proc Natl Acad Sci U S A., 106(13):5181-6
Wu, J. I., Lessard, J., and Crabtree, G. R. (2009) Understanding the words of chromatin remodeling. Cell, 136(2):200-6.
Wu, J. I., Lessard, J., Olave, I. A., Qiu, Z. Ghosh, A., Graef, I. A., and Crabtree, G. R. (2007). Regulation of dendritic development by neuron-specific chromatin remodeling complexes. Neuron 56, 94-108 (featured in Leading Edge Cell 131, 199; Research Focus in Trends in Cell Biology 18, 48-51; Featured article in Nature Neuroscience Gateway Oct. 2007).
Lessard, J.*, Wu, J. I.*, Ranish, J. A., Wan, M., Winslow, M. M., Staahl, B. T., Wu, H., Aebersold, R., Graef, I. A., and Crabtree, G. R. (2007). An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron 55, 201-215 (cover and preview Neuron 55, 171-173).