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"ROLE OF THE SWI/SNF CHROMATIN REMODELING COMPLEX IN TRANSCRIPTIONAL REGULATION OF OSTEOBLAST AND ADIPOCYTE DIFFERENTIATION"

by
Fuhua Xu
Interdisciplinary Biomedical Sciences Program
M.S. 2004, Creighton University, Omaha, NE
B.S. 1996, China Agricultural University, Beijing, China


Thesis Advisor: Elizabeth Moran, Ph.D.
Professor
Department of Orthopaedics

Thursday, March 14, 2013
2:00 P.M., Cancer Center G1196


Abstract

Unfolding of the gene expression program that converts precursor cells to their terminally differentiated counterparts is critically dependent on the nucleosome-remodeling activity of the mammalian SWI/SNF complex. The complex can be powered by either of two alternative ATPases, BRM or BRG1. BRG1 is required for tissue-specific gene expression in every system tested, while BRM plays a modulating or auxiliary role. BRG1 can be the ATPase of either the BAF complex (only associated with the ARID1A or ARID1B subunits) or the PBAF complex (associated with a distinct ARID2 subunit). The BAF complex is the most commonly studied iteration of BRG1-SWI/SNF, while PBAF has received very little specific attention. I have used an osteoblast differentiation model to study the distinct role of PBAF. Depletion of ARID2 results in loss of expression of the commitment markers, Bmp4 and Fgfr2, and severely impairs induction of the key osteoblast markers Alpl and Bglap, as well as progression to a mineralizing phenotype. BRG1-SWI/SNF also participates in transcriptional repression, restraining premature expression of late-stage markers of osteoblast maturation such that BRG1 deficiency results in constitutive induction of the late stage markers Dmp1 and Phex in undifferentiated cells. Deficiency of ARID2 does not affect this activity of BRG1, indicating the repression function is linked with BAF, not with PBAF. Taken together, these findings suggest the PBAF subset of SWI/SNF contributes importantly to maintaining cellular identity and activating tissue-specific gene expression. Though rarely studied as a specific entity, PBAF may be the major tissue-specific gene-activating configuration of SWI/SNF.

Osteoblasts and adipocytes are derived from a common precursor in bone marrow stromal cells. An improper balance of maturation along the osteoblast versus the adipocyte lineage underlies many skeletal diseases. BRG1 is required for differentiation along all lineages, but previous work in this lab showed BRM-SWI/SNF represses osteoblast differentiation. To understand control of the osteoblast/adipocyte choice it is critical to elucidate the roles of BRM and BRG1 in adipogenesis. To address this question, I generated BRM and BRG1 stable knockdown lines in 3T3-L1 preadipocytes. In contrast to their opposing roles in osteoblasts, both BRM and BRG1 are required for adipogenesis. Depletion of either BRM or BRG1 has a similar effect in inhibiting adipogenesis and expression of key early and late adipocyte markers. The finding of opposing roles for BRM in osteoblast versus adipocyte differentiation may provide a way to perturb the fate of BMSCs, to increase bone formation and reduce bone marrow adiposity in vivo. Further study in an animal model is warranted.


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