We discovered that the Brg1 chromatin remodeling protein is frequently mutated in human lung cancer. We showed that gene expression profiles are heavily disrupted in lung cells harboring these mutations, and further showed that restoration of wild type Brg1 function will partially restore normal expression profiles. We have developed dominant negative forms of the Brg1, INO80, Snf2h, and CHD4 human chromatin remodeling proteins, and have developed individual cell lines expressing these dominant negative activities under inducible (tetracycline) regulation. We have characterized the biochemical activity of these mutant complexes, and shown that they are each defective in nucleosome remodeling activity. We are studying the potential role of these remodeling systems in the action of nuclear receptors at specific sites of remodeling genome wide. We have discovered that multiple remodeling complexes function at almost all regulatory elements in the murine genome.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010646-10
Application #
8763161
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2013
Total Cost
$341,548
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Morris, Stephanie A; Baek, Songjoon; Sung, Myong-Hee et al. (2014) Overlapping chromatin-remodeling systems collaborate genome wide at dynamic chromatin transitions. Nat Struct Mol Biol 21:73-81
Miranda, Tina B; Morris, Stephanie A; Hager, Gordon L (2013) Complex genomic interactions in the dynamic regulation of transcription by the glucocorticoid receptor. Mol Cell Endocrinol 380:16-24