ROLE OF CHROMATIN REMODELING IN GROWTH CONTROL

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The state of chromatin at any given gene is a critical aspect of its regulation. Chromatin establishes a repressive environment that is inhibitory to transcription, from prevention of initial factor binding to inhibition of elongation. This repressive effect appears to be relieved by ATP-dependent chromatin remodeling complexes and enzymes that acetylate the histone tails, and enhanced by complexes of repressor proteins, histone deacetylases, and other factors. Recent evidence suggests that two chromatin remodeling complexes, hSWI/SNF and NRD, might be essential for growth control mechanisms through recruitment by the retinoblastoma family of tumor suppressor proteins. Although this evidence indicates an important role for these complexes, it tells us very little about their mechanism of action. Current evidence, from my work and others', suggest potential mechanisms by which remodeling complexes could activate, as well as repress, transcription. The purpose of the research described here is to analyze the mechanisms of the two human chromatin remodeling complexes, hSWI/SNF and NRD, to better understand their potential effects on transcriptional control. These complexes will be assayed for their ability to affect nucleosome mobility and higher-order structures, and for their effects to be influenced by transcription factors and chromatinassociated proteins. The role of chromatin remodeling in facilitating the second function of NRD, histone deacetylation will also be examined. The ability of the retinoblastoma protein to interact with these complexes to recruit them to promoters will be examined in vitro and in vivo, with the aim of establishing a strong model system for examining the role of chromatin remodeling in growth control decisions and general transcriptional regulation.