Remodeling of chromatin structures precedes or occurs concurrently with the activation of gene transcription. These structural alterations are often initiated by the binding of sequence-specific transcription factors and facilitated by the action of multiprotein complexes which disrupt the structure of nucleosomes of modify histone proteins. These proteins are intimately linked to transcription control and implicated in the development of human cancers. Subunits of the ATP-dependent nucleosome disrupting SWI/SNF complex and histone acetyltransferase complexes interact with viral oncogene and tumor suppressor gene products. This proposal is to analyze the biochemical functions of the yeast SWI/SNF complex and yeast histone acetyltransferase complexes in the process of chromatin remodeling.
The specific aims are: 1. Analyze the interactions of the SWI/SNF complex with nucleosomes, its activities in stimulating the binding of transcription factors and the disruption of nucleosomes. These studies will analyze the contributions of histone proteins to nucleosome interactions with the SWI/SNF complex and the functions of the SWI/SNF complex in facilitating the loss of histones from transcription factor-bound DNA sequences. 2. Purification of several recently identified native histone acetyltransferase complexes from yeast. This work will purify native complexes which acetylate nucleosomal histones H3 and H2B, contain Gcn5p as a catalytic subunit and appear to contain additional ADA and Spt gene products. Characterization and purification of additional histone acetyltransferase complexes that acetylate different nucleosomal histones will also be carried out. 3. Functional analysis of native histone acetyltransferase complexes. This work will characterize the substrate specificity of the native complexes and their functions in enhancing transcription factor binding to nucleosomes. Additional experiments will analyze the interactions of these complexes with transcriptional activation domains and the ability of such interactions to target histone acetylation to acetylation to specific nucleosomes within chromatin. 4. Analysis of synergistic and functional interactions of the SWI/SNF and native histone acetyltransferase complexes. These experiments will determine how nucleosome disruption by SWI/SNF alters histone acetylation and visa versa. The combined effects of these complexes in chromatin remodeling and in stimulating the binding of basal transcription factors to chromatin during transcription activation will be determined.
| 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 |
| Venkatesh, Swaminathan; Workman, Jerry L (2013) Set2 mediated H3 lysine 36 methylation: regulation of transcription elongation and implications in organismal development. Wiley Interdiscip Rev Dev Biol 2:685-700 |
| Becker, Peter B; Workman, Jerry L (2013) Nucleosome remodeling and epigenetics. Cold Spring Harb Perspect Biol 5: |
| Smolle, Michaela; Workman, Jerry L; Venkatesh, Swaminathan (2013) reSETting chromatin during transcription elongation. Epigenetics 8:10-5 |
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