The Biological Significance of BRG1 Mutations Public Deposited

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  • March 20, 2019
Creator
  • Bartlett, Chris
    • Affiliation: School of Medicine, Curriculum in Toxicology
Abstract
  • Eukaryotic organisms package DNA into chromatin for compact storage in the cell nucleus, but this packaging process results in transcriptional repression of genes. Chromatin remodeling complexes have evolved to overcome the transcriptional repression caused by chromatin packaging of DNA into nucleosomes by histones. One example of a chromatin remodeling complex is the SWI/SNF complex in yeast which uses ATP to drive the chromatin apart and make DNA accessible to transcription factors. The yeast SWI2 protein was discovered as the catalytic subunit of the yeast SWI/SNF chromatin remodeling complex and is required for the complex to counteract the repressive nature of chromatin. BRG1 and BRM, SWI2 homologs, are part of human chromatin remodeling complexes and have been shown to play a redundant role in the regulation of certain cell cycle and cellular adhesion genes, as well as cellular pathways. Recent studies showing loss of BRG1 in human tumor cell lines and primary tissue samples, BRG1 mutations in human tumor cell lines, a requirement for BRG1 in Rb mediated arrest, and development of apocrine like tumors by BRG1 heterozygous mice, have implicated a role for BRG1 in cancer development. However, little is known about BRG1's role in the cell and the subsequent mechanistic changes cells experience after loss of BRG1 function. To better understand the role of BRG1 in cancer development we studied previously characterized human tumor cell lines with BRG1 point mutations. We found that the mutations in BRG1 resulted in the loss of CD44 and E-cadherin gene regulation by the complex and disruption of Rb mediated arrest. We next wanted to investigate the mechanism by which loss of BRG1 function effected gene regulation and Rb mediated arrest. We observed that reintroduction of BRG1 into the cells, or treatment with 5-azacytidine, demethylated bases in the CD44 and E-cadherin promoter, leading to re-expression of the genes. Loss of functional BRG1 may lead to aberrant methylation of target gene promoters and cancer development and/or progression through silencing of tumor suppressor genes.
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  • In Copyright
Advisor
  • Weissman, Bernard
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2006
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