The growth, differentiation and transformation of human cells is largely governed by the of cellular gene expression. One of the primary levels at which this regulation is applied is at the level of transcription. The importance of transcription control to cellular growth is evidenced by the observation that numerous nuclear oncogene products are regulatory transcription factors. In addition to the function of these and other regulatory transcription factors, structural, biochemical and genetic studies have indicated that chromosomal structural proteins also play a crucial role in the regulation of transcription. These proteins appear to prevent the interaction of RNA polymerases and basal factors with promoters of genes in cells where those genes are necessarily repressed. The long term goal of this application is to elucidate mechanisms by which this repression occurs and how regulatory transcription factors overcome this repression to activate specific genes in a programmed pattern of gene expression. Understanding the interactions of regulatory transcription factors with chromosomal structural proteins is a necessary step in elucidating the details of transcription control. This proposal is to perform a series of detailed biochemical studies on the interaction of different transcription factors with nucleosomes (the primary level of chromosome structure). Direct binding studies will be performed with purified factors and nucleosome core particles reconstituted with purified histones. These studies will reveal the ability of factors with different binding domains to interact with nucleosome DNA. Protein analysis of the purified bound complexes will reveal if the binding of some transcription factors leads to displacement of histones. In addition these studies will reveal if factors cooperate in binding to nucleosomes and the role of different factors in such processes. These results may indicate whether facilitated binding of to nucleosomes is a mechanism by which the combined action of multiple factors regulates transcription. Further studies will address the functional consequence of factors binding to nucleosomes in the activation of transcription. The function of acidic, glurich and pro-rich activation domains in overcoming nucleosome-mediated repression of transcription will be addressed (in fusion proteins with GAL4 and native factors). The role of histone modifications (i.e. acetylation) will be addressed in similar factor binding and transcription studies to investigate their role in transcription control.
| Dutta, Arnob; Workman, Jerry L (2017) In Vitro Assembly of Nucleosomes for Binding/Remodeling Assays. Methods Mol Biol 1528:1-17 |
| Dutta, Arnob; Sardiu, Mihaela; Gogol, Madelaine et al. (2017) Composition and Function of Mutant Swi/Snf Complexes. Cell Rep 18:2124-2134 |
| Venkatesh, Swaminathan; Li, Hua; Gogol, Madelaine M et al. (2016) Selective suppression of antisense transcription by Set2-mediated H3K36 methylation. Nat Commun 7:13610 |
| Venkatesh, Swaminathan; Workman, Jerry L (2015) Histone exchange, chromatin structure and the regulation of transcription. Nat Rev Mol Cell Biol 16:178-89 |
| Kumar, Ram P; Dobi, Krista C; Baylies, Mary K et al. (2015) Muscle cell fate choice requires the T-box transcription factor midline in Drosophila. Genetics 199:777-91 |
| Khan, Dilshad H; Gonzalez, Carolina; Cooper, Charlton et al. (2014) RNA-dependent dynamic histone acetylation regulates MCL1 alternative splicing. Nucleic Acids Res 42:1656-70 |
| Dutta, Arnob; Gogol, Madelaine; Kim, Jeong-Hoon et al. (2014) Swi/Snf dynamics on stress-responsive genes is governed by competitive bromodomain interactions. Genes Dev 28:2314-30 |
| Smolle, Michaela; Workman, Jerry L; Venkatesh, Swaminathan (2013) reSETting chromatin during transcription elongation. Epigenetics 8:10-5 |
| Suganuma, Tamaki; Workman, Jerry L (2013) Chromatin and signaling. Curr Opin Cell Biol 25:322-6 |
| Venkatesh, Swaminathan; Workman, Jerry L; Wahlgren, Mats et al. (2013) Malaria: Molecular secrets of a parasite. Nature 499:156-7 |
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