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 Zhong Wang, PhD |
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Science - Chromatin Remodeling, Gene Expression and Mammalian Development
Chromatin remodeling complexes facilitate nucleosome mobilization and assist transcription factors to access the DNA template, thus representing a vitally important class of co-regulatory factors for directing spatial and temporal patterns of gene expression during development. BAF and PBAF are two closely related SWI/SNF remodeling complexes in mammalian cells. BAF and PBAF share eight common subunits but are distinguished by three polypeptide components: BAF180 (unique to PBAF), BAF250 and OSA2 (unique to BAF). These unique subunits may represent key regulatory components that functionally distinguish PBAF from BAF. The objective of the research in our lab is to dissect the putatively distinct transcriptional networks dependent upon either BAF or PBAF in regulating gene expression, organ development and pathogenesis, using a mouse model system.
BAF180, Heart Development, and RA signaling: Our current research indicates that BAF180 deficiency leads to severe hypoplastic ventricle development and trophoblast placental defects in mouse embryos. Tetraploid and ES cell embryonic aggregation experiments revealed that the heart defects are likely a direct result of BAF180 ablation, and not an indirect consequence of the trophoblast placental defects. I then identified potential target genes for BAF180-dependent regulation in heart development, such as S100A13 as well as retinoic acid (RA)-induced targets RARb2 and CRABPII. Importantly, BAF180 is recruited to the promoter of these target genes and BAF180 deficiency affects the RA-response for CRABPII and RARb2. And lastly, BAF180 is essential for the proper development of coronary vessels derived from epicardium. These studies reveal unique functions of BAF180 (PBAF) in cardiac chamber maturation, and suggest that at least in part, the heart defects in BAF180 null embryos may be due to a disruption of RA signaling.
Investigate BAF-specific BAF250- and OSA2-mediated gene expression during development: Our recent studies indicate that mice lacking BAF250 or OSA-2 show dramatically different developmental defects compared to the BAF180 knockout mice. For example, BAF250 haploid insufficiency results in heart and neural tube closure defects. These data suggest that BAF and PBAF indeed perform distinct functions in vivo. Interestingly, there are also distinct phenotypes associated with BAF250 and OSA-2 deficient mice, suggesting that there could be sub-complexes of BAF that either harbor BAF250 or OSA-2 as regulatory subunits. Moreover, in collaboration with Dr. William C. Skarnes, we discovered that complete ablation of BAF-specific subunit BAF250 in mouse ES cells unexpectedly promotes differentiation and severely inhibits normal proliferation of these cells under normal ES cell culture conditions.
Future detailed analyses of these unique and distinguishing subunits in different SWI/SNF complexes should ultimately reveal how these complex chromatin remodeling cofactors work individually or in concert to guide gene expression, cell growth and organ development. Insights into the molecular mechanisms governing these chromatin remodeling complexes will provide potential targets for developing small molecule drugs and modern therapies to treat various human diseases, such as heart failure, neural tube defects, or cancer.
Development of high efficient conditional knockout and knockin strategies for mouse organ and human ES cell studies: During our in vivo studies for BAF and PBAF complexes, we have developed a series of knockout strategies for ablating gene activity in the mouse tissues, ES cell or somatic cell lines. We have successfully and efficiently modified the two copies of BAF250 in mouse ES cell lines. We are currently modifying this strategy to in situ knock-in genes of interest with inducible expression. We are also applying these new methods to human ES cell studies.
Collaborative Relationships:
Zhong Wang's lab is part of the Stem Cell Biology + Therapy Program.
Selected Publications:
Gao X, Tate P, Hu P, Tjian R, Skarnes WC, Wang Z. ES cell pluripotency and germ layer formation require the SWI/SNF chromatin remodeling component BAF250a. Proc. Natl. Acad. Sci. U.S.A. 2008; In press.
*Yan Z, *Wang Z, *Sharova L, Sharov A.A, Ling C, Piao Y, Aiba K, Matoba R, Wang W, Ko MSH. The BAF250b-associated SWI/SNF chromatin-remodeling complex is required for the maintenance of undifferentiated mouse embryonic stem cells. Stem Cells. 2008; In press. *These authors contributed equally to this work.
Martin-Puig S, Wang Z, Chien KR. Lives of a heart cell: Tracing the origins of cardiac progenitors. Cell Stem Cell. 2008; 2(4).
Huang, X., Gao, X., Trelles, R., Ruiz-Lozano, P., and Wang, Z. Coronary development is regulated by ATP-dependent SWI/SNF chromatin remodeling component BAF180. Submitted (under 2nd revision).
Wang Z, Zhai W, Richardson JA, Olson EN, Meneses JJ, Firpo MT, Kang C, Skarnes WC, Tjian R. Polybromo protein BAF180 functions in mammalian cardiac chamber maturation. 2004; Genes Dev. 18:3106-3116.
Click here to view Zhong Wang's previous publications.
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