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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Salomon-Kent, Ronit; Marom, Ronit; John, Sam et al. (2015) New Face for Chromatin-Related Mesenchymal Modulator: n-CHD9 Localizes to Nucleoli and Interacts With Ribosomal Genes. J Cell Physiol 230:2270-80
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
Stavreva, Diana A; Varticovski, Lyuba; Hager, Gordon L (2012) Complex dynamics of transcription regulation. Biochim Biophys Acta 1819:657-66
Hager, Gordon L; Varticovski, Lyuba (2012) Chromatin in time and space. Biochim Biophys Acta 1819:631
Romero, Octavio A; Setien, Fernando; John, Sam et al. (2012) The tumour suppressor and chromatin-remodelling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer. EMBO Mol Med 4:603-16
Wiench, Malgorzata; Miranda, Tina B; Hager, Gordon L (2011) Control of nuclear receptor function by local chromatin structure. FEBS J 278:2211-30
Wiench, Malgorzata; Hager, Gordon L (2010) Expanding horizons for nuclear receptors. EMBO Rep 11:569-71