Chromatin regulation plays important roles in stem cell differentiation, tissue development and tumorigenesis. Together with histone modification and DNA methylation, ATP-dependent chromatin remodeling regulates DNA accessibility to transcription factors and determines the competence of the cells to environmental signals. During vertebrate neural development, multipotent neural stem cells/progenitors have the capability to both self-renew and to generate all the neuronal and glial cell types. The transition from multipotent proliferating neural stem cells/progenitors to neurons is accompanied with permanent exit of cell cycle and formation of distinctive patterns of axons and dendrites. Coordinated changes of chromatin structures and gene activities play a key role in this transition. We are interested in the function of the chromatin regulation in neural stem cell self-renewal, differentiation, as well as post-mitotic neuronal development. The immediate focus is the prototypical SWI/SNF-like BAF (Brg/Brm associated factors) ATP-dependent chromatin remodeling complexes. Our previous studies have shown a subunit composition change of BAF complexes during neural development and that neural progenitor npBAF complexes are essential for the self-renewal and maintenance of neural stem/progenitor cells, while neuron-specific nBAF complexes are required for activity-dependent dendritic outgrowth, a unique aspect of post-mitotic neuron development. A combination of molecular biology, biochemistry and genetic approaches will be used to investigate the molecular mechanisms of chromatin regulation of gene expression essential for neural development.
1. Function of chromatin remodeling in key signaling pathways that regulate neural development The epigenetic status of gene promoters determines their accessibility to transcription factors and is critical for signaling pathways to produce specific outcomes in different cell types or at different developmental stages. We are interested in the function of BAF complexes in key signaling pathways during neural development and will use this model to understand how chromatin remodeling determines the competence of stem cells to certain signals and their commitment to specific lineages. We will use genetically engineered mouse models to study the function of BAF complexes in key signaling pathways that regulate progenitor proliferation, neural patterning and glial differentiation. We will investigate the interactions of BAF complexes with the key factors in the signaling pathways and how the target genes involved in neural development are regulated.
2. Function of nBAF complexes in neuronal activity-dependent transcription regulation Activity-dependent transcription 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 nBAF complexes regulate activity-dependent dendritic outgrowth. We plan to use a proteomics approach to identify changes of subunits/interacting proteins or their modifications upon Ca2 influx. After localizing such modifications, efforts will be made to identify upstream enzymes and downstream targets to reveal the complete signaling pathway from neuronal activities to chromatin remodeling.
3. Explore the molecular mechanisms of chromatin control of neural stem cell differentiation The transition from proliferating neural stem cells/progenitors to post-mitotic neurons is accompanied by an epigenetic switch from BAF45a/53a containing npBAF complexes to BAF45b/53b containing nBAF complexes. We plan to study the biological significance of this switch in regulating neural stem cell/progenitor proliferation and differentiation and use this as a starting point to explore the molecular mechanism of epigenetic control of stem cell differentiation. Questions will be addressed with a combination of genomics, proteomics and genetics approaches.
RESEARCH INTERESTS
Chromatin remodeling
neural development
neural stem cell differentiation
activity-dependent gene expression
RECENT PUBLICATIONS
Stankunas, K., Hang, C.T., Tsun, Z.Y., Chen, H., Lee, N.V., Wu J.I., Shang, C., Bayle, J.H., Shou, W., Iruela-Arispe, M.L., Chang, C.P., "Endocardial Brg1 represses ADAMTS1 to maintain the microenvironment for myocardial morphogenesis." Dev. Cell, 14:298-311, 2008
Wu, J. I., Rajendra, R., Barsi, J.C., Durfee, L., Benito, E., Gao, G., Kuruvilla, M., Hrdlickova, R., Liss, A. S., Artzt, K., "Targeted disruption of Mib2 causes exencephaly with a variable penetrance" Genesis, 45:722-727, 2007
Wu, J. I., Centilli, M. A., Vasquez G., Young, S., Scolnick, J., Durfee L. A., Spearow, J. L., Schwantz S. D., Rennebeck G., and Artzt K., "tint maps to mouse chromosome 6 and may interact with a notochordal enhancer of Brachyury" Genetics, 177:1151-1161, 2007
Wu, J. I., Lessard, J., Olave, I. A., Qiu, Z. Ghosh, A., Graef, I. A., and Crabtree, G. R., "Regulation of dendritic development by neuron-specific chromatin remodeling complexes" Neuron, 56:94-108, 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., "An essential switch in subunit composition of a chromatin remodeling complex during neural development" Neuron, 55:201-215, 2007
SIGNIFICANT PUBLICATIONS
Wu, J. I., Lessard, J., Olave, I. A., Qiu, Z. Ghosh, A., Graef, I. A., and Crabtree, G. R., "Regulation of dendritic development by neuron-specific chromatin remodeling complexes" Neuron, 56:94-108, 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., "An essential switch in subunit composition of a chromatin remodeling complex during neural development" Neuron, 55:201-215, 2007
Barsi, J.C.*, Rajendra, R.*, Wu, J.I.*, and Artzt, K., "Mind bomb 1 is a ubiquitin ligase essential for mouse embryonic development and Notch signaling" Mech. Dev., 122:1106-1117, 2005
Wu, J.I., Reed R.B., Grabowski, P. J., and Artzt, K., "The function of quaking in myelination: alternative splicing regulation" Proc. Natl. Acad. Sci. USA, 99:4233-4238, 2002
Point and right click (click and hold for Mac users) your mouse onand select "Save this link (or target) as..." option to save the file to your local computer.
and select "Save this link (or target) as..." option to save the file to your local computer.