The mechanisms by which eukaryotes regulate gene expression are important for understanding many complex biological phenomena including human diseases. Prevention and treatment of such diseases have been and will continue to be improved by basic knowledge of gene regulation, especially because molecular mechanisms of transcriptional initiation are highly conserved in eukaryotic organisms ranging from human to yeast. This proposal will continue to investigate the following basic issues concerning molecular mechanisms of transcriptional regulation, primarily in yeast, by combining chromatin immunoprecipitation (ChIP), molecular genetics, biochemistry, and genomics. 1) Mechanisms of activator-specific recruitment of TFIID and growth-regulation of ribosomal protein (RP) genes: determining functional relationships among proteins associating with RP promoters;defining the activator-TAF interactions in molecular terms. 2) Functional dissection of the Mediator complex: activator-specificity of recruitment to enhancer;Mediator subunits and surfaces necessary for activator-mediated recruitment and connection to the Pol II machinery;addressing whether Mediator truly has a general and required function for Pol II transcription. 3) Genome accessibility to transcription factors: high resolution mapping of nucleosome positions over the entire yeast genome using samples from several yeast species and chromatin reconstituted in vitro;genetic analysis of the mechanism of preferential positioning within coding regions;examining whether principles of nucleosome positioning in yeast extend to human cells. 4) Association of DNA-binding proteins to target sites in vivo: CnlP and microarray technology to examine the effect of protein concentration or presence of activation domains;determining how bZIP proteins with similar DNA-binding specificities in vitro have different target genes in vivo. Evolutionary conservation of binding sites of bZIP proteins in several yeast species and also by human-chimp and human-mouse comparisions. 5) Mechanisms and biological significance of novel genetic elements (ETC loci) containing incomplete Pol III transcription complexes in vivo including examination of a role of the ETC loci in nuclear positioning. 6) Transcriptional elongation using novel in vivo assays: co-association of elongation factors with mRNA coding regions;functional redundancy of elongation factors in terms of Pol II elongation rate and processiyity;role of Swi/Snf nuclepspme-remodeling complex in elongation;initiation vs. elongation as a limiting step for Pol II transcription in vivo;effects of temperature and growth conditions on Pol II transcription. 7) Mechanism by which Hog1 MAP kinase acts as an elongation factor specific for osmotically induced genes: effect of Hog1 on elongation rate and processivity;DNA or RNA sequence

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics B Study Section (MGB)
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Tompkins, Laurie
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Harvard University
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Jin, Yi; Eser, Umut; Struhl, Kevin et al. (2017) The Ground State and Evolution of Promoter Region Directionality. Cell 170:889-898.e10
Petrenko, Natalia; Jin, Yi; Wong, Koon Ho et al. (2017) Evidence that Mediator is essential for Pol II transcription, but is not a required component of the preinitiation complex in vivo. Elife 6:
Miotto, Benoit; Ji, Zhe; Struhl, Kevin (2016) Selectivity of ORC binding sites and the relation to replication timing, fragile sites, and deletions in cancers. Proc Natl Acad Sci U S A 113:E4810-9
Petrenko, Natalia; Jin, Yi; Wong, Koon Ho et al. (2016) Mediator Undergoes a Compositional Change during Transcriptional Activation. Mol Cell 64:443-454
Jin, Yi; Geisberg, Joseph V; Moqtaderi, Zarmik et al. (2015) Mapping 3' mRNA isoforms on a genomic scale. Curr Protoc Mol Biol 110:4.23.1-17
Wong, Koon Ho; Jin, Yi; Struhl, Kevin (2014) TFIIH phosphorylation of the Pol II CTD stimulates mediator dissociation from the preinitiation complex and promoter escape. Mol Cell 54:601-12
Moqtaderi, Zarmik; Geisberg, Joseph V; Struhl, Kevin (2014) Secondary structures involving the poly(A) tail and other 3' sequences are major determinants of mRNA isoform stability in yeast. Microb Cell 1:137-139
Geisberg, Joseph V; Moqtaderi, Zarmik; Fan, Xiaochun et al. (2014) Global analysis of mRNA isoform half-lives reveals stabilizing and destabilizing elements in yeast. Cell 156:812-24
Struhl, Kevin; Segal, Eran (2013) Determinants of nucleosome positioning. Nat Struct Mol Biol 20:267-73
Moqtaderi, Zarmik; Geisberg, Joseph V; Jin, Yi et al. (2013) Species-specific factors mediate extensive heterogeneity of mRNA 3' ends in yeasts. Proc Natl Acad Sci U S A 110:11073-8

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