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Jiang Wu, Ph.D.
Ph.D, University of Texas at Austin – 2001
Assistant Professor, Departments of Physiology and Developmental Biology
Endowed Scholar, UT Southwestern Medical Center
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Office: 214-648-1824
Fax: 214 648-1960
Lab: 214-648-1823
Building ND, Room 5.214B
Email: Jiang Wu
Chromatin Regulation of Neural Development
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.
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.
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.
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.
Selected references
Wu, J. I., Lessard, J., and Crabtree, G. R. (2008) Understanding the words of chromatin remodeling. Cell, in press.
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. (2008) Endocardial Brg1 represses ADAMTS1 to maintain the microenvironment for myocardial morphogenesis. Dev. Cell 14, 298-311.
Wu, J. I., Rajendra, R., Barsi, J.C., Durfee, L., Benito, E., Gao, G., Kuruvilla, M., Hrdlicková, R., Liss, A. S., Artzt, K. (2007) Targeted disruption of Mib2 causes exencephaly with a variable penetrance. Genesis 45, 722-727.
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. (2007). tint maps to mouse chromosome 6 and may interact with a notochordal enhancer of Brachyury. Genetics 177, 1151-1161
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).
*: Equal contribution.
Wu, J. I. and Crabtree, G. R. (2007) Cell signaling. Nuclear actin as choreographer of cell morphology and transcription. Science 316:1710-1711
Barsi, J.C.*, Rajendra, R.*, Wu, J.I.*, and Artzt, K. (2005) Mind bomb 1 is a ubiquitin ligase essential for mouse embryonic development and Notch signaling. Mech. Dev. 122: 1106-1117. (cover)
*: Equal contribution.
Wu, J.I., Reed R.B., Grabowski, P. J., and Artzt, K. (2002) The function of quaking in myelination: alternative splicing regulation. Proc. Natl. Acad. Sci. USA 99: 4233-4238.
Wu, J., Zhou L., Tonissen k. , Tee R., and Artzt, K. (1999) The quakingI-5 (QKI-5) protein has a novel nuclear localization signal and shuttles between the nucleus and the cytoplasm. J. Biol. Chem. 274: 29202-29210.
