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"ANALYZING BRM-SWI/SNF AS TARGET TO REGULATE LINEAGE CHOICE IN MESSENCHYMAL STEM CELLS"

by
Kevin Hong Nguyen
Interdisciplinary Biomedical Sciences Program
B.A. (2006) Rutgers, The State University of New Jersey


Thesis Advisor: Elizabeth Moran, Ph.D.
Fred F. Buechel Professor for Orthopaedic Research
Department of Orthopaedics

Wednesday, April 9, 2014
1:00 P.M., Cancer Center, G-1196


Abstract

he chromatin remodeling complex SWI/SNF, with its core ATPase BRG1, is required for tissue-specific gene expression. A subset of SWI/SNF, powered by the alternative ATPase BRM, generally has auxiliary effects. In osteoblast precursors, BRM-SWI/SNF represses tissue-specific gene expression, preventing premature induction of osteogenic genes whose activation is BRM-independent. The role of BRM in other lineages derived from bone marrow stromal cells (BMSCs) is largely unknown, but its role in adipocyte differentiation is of particular interest because an improper balance of adipocyte versus osteoblast differentiation underlies certain skeletal pathologies, such as osteoporosis. To address this question, stable knockdown lines targeting BRM were generated in the C3H10T1/2 mesenchymal stem cell line. While osteoblasts and adipocytes share a common precursor in bone marrow stromal cells (BMSCs), they have an inverse relationship during differentiation and maturation. Therefore analyzing the role of BRM-SWI/SNF in regulation of lineage selection in BMSCs is key. Results here show depletion of BRM inhibits adipogenesis and expression of key early and late adipocyte markers. On the other hand, depletion of BRM accelerates osteoblast differentiation and constitutive expression of osteogenic markers such as Fgfr2, Alpl, and Dmp1. BRM plays the role of an activator during adipogenesis and a repressor during osteogenesis. The finding of opposing roles for BRM in osteoblast versus adipocyte differentiation suggests a future possibility of targeting BRM to perturb the fate of BMSCs so as to increase bone formation and reduce bone marrow adiposity in vivo.


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