Inactivating mutations in the SNF5 gene result in aggressive cancers in children and a familial cancer predisposition syndrome. As a core member of the SWI/SNF ATPase chromatin remodeling complex, which regulates transcription by repositioning nucleosomes, SNF5 represents a newly recognized type of tumor suppressor. Accumulating evidence suggests that perturbation of the SWI/SNF complex may have a widespread role in the genesis of numerous types of common cancers including those of breast, lung, prostate and pancreas. Additionally, mouse models have further highlighted the crucial role of Snf5 in preventing oncogenesis, as loss of Snf5 results in rapid, completely penetrant tumor formation. While these data have established a crucial role for the SWI/SNF complex in regulating growth and preventing oncogenic transformation, the mechanistic basis for this activity is largely unknown. Increasing data support the concept that cancer stem cells, the rare subset of tumor cells which drive tumorigenesis, achieve immortality in part by activating gene expression pathways normally reserved for stem cells. In addition to roles in tissue and lineage specific differentiation programs, extensive evidence also supports a role for the Swi/Snf complex in maintaining the pluripotency and survival of embryonic stem (ES) cells. We hypothesize that the Swi/Snf complex serves a key role in regulating the balance between self-renewal and differentiation and that this contributes to its tumor suppressor activity. Our goal is to define the role of Swi/Snf in ES cell pluripotency and self-renewal by addressing the following specific aims: (1) What promoters are bound by Swi/Snf in ES cells? (2) What are the effects of inactivation of Snf5, a core Swi/Snf subunit, upon pluripotency and self-renewal in ES cells? (3) How do Swi/Snf and PcG complexes cooperate to control gene expression in ES cells? Relevance: Accumulating data suggest that cancer arises from disruption of the genetic programs which control growth in stem cells;stem cells are rare cells in the body that are capable of giving rise to many different types of tissues and are thus the master controllers of development. Recent evidence also suggests that the SWI/SNF complex serves a critical role in regulating the growth and identity of stem cells. A detailed study of the role of the Swi/Snf complex in embryonic stem cells will likely shed important insights to help us better understand gene regulation in embryonic stem cells, in tumor cells which have acquired stem cell like properties, and also how defects in the Swi/Snf complex can lead to cancer development.
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