? The genome of an organism encodes thousands of genes that must be appropriately expressed for normal cellular functioning. A thorough understanding of the mechanistic details of genome-wide transcriptional control is important, as dozens of transcription factors have been implicated in the etiology of many human diseases including cancer. Transcription factors, as well as their mechanisms of function, are highly conserved between yeast and mammals. This proposal is aimed at generating a genome-wide, detailed, and systematic molecular understanding of transcriptional regulation in yeast during specific physiological responses. A functional genomic approach will be used to study the transcriptional reprogramming of the yeast genome during the responses to heat shock and stationary phase stress. For selected transcription factors that mediate stress responses in yeast, their downstream targets will be determined using a variety of approaches. The relative influence of chromatin structure and binding site complexity on transcriptional specificity will be determined. Simultaneously, we will apply a variety of computational methods to organize, analyze and interpret the large body of resulting data. They will be directed towards identifying functional transcriptional regulatory networks underlying global responses, as well as identifying cis-regulatory elements and aspects of chromatin structure that confer specificity. Regulatory networks will be modelled, experimentally validated, and extended to explain global transcriptional profiles. This work will test several hypotheses about genome-wide transcriptional regulation, including i) global transcriptional programs can be reconstructed in terms of their composite transcriptional pathways and networks mediated by individual transcriptional regulators ii) transcriptional specificity is achieved through a combination of cis-regulatory elements and local chromatin structure at promoters, iii) different members of multi-subunit complexes may have distinct roles in mediating transcriptional responses. Given the conservation of transcription factors and mechanisms between yeast and mammals, the results are likely to be significant in understanding and further studying transcriptional control in the human genome. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095548-05
Application #
7367857
Study Section
Genome Study Section (GNM)
Program Officer
Couch, Jennifer A
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2008-03-01
Budget End
2009-03-31
Support Year
5
Fiscal Year
2008
Total Cost
$256,552
Indirect Cost
Name
University of Texas Austin
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Bagchi, Dia N; Iyer, Vishwanath R (2016) The Determinants of Directionality in Transcriptional Initiation. Trends Genet 32:322-333
Zhang, Dingxiao; Park, Daechan; Zhong, Yi et al. (2016) Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer. Nat Commun 7:10798
Dekker, Joseph D; Park, Daechan; Shaffer 3rd, Arthur L et al. (2016) Subtype-specific addiction of the activated B-cell subset of diffuse large B-cell lymphoma to FOXP1. Proc Natl Acad Sci U S A 113:E577-86
Park, Daechan; Shivram, Haridha; Iyer, Vishwanath R (2014) Chd1 co-localizes with early transcription elongation factors independently of H3K36 methylation and releases stalled RNA polymerase II at introns. Epigenetics Chromatin 7:32
Park, Daechan; Morris, Adam R; Battenhouse, Anna et al. (2014) Simultaneous mapping of transcript ends at single-nucleotide resolution and identification of widespread promoter-associated non-coding RNA governed by TATA elements. Nucleic Acids Res 42:3736-49
Park, Daechan; Lee, Yaelim; Bhupindersingh, Gurvani et al. (2013) Widespread misinterpretable ChIP-seq bias in yeast. PLoS One 8:e83506
Iyer, Vishwanath R (2012) Nucleosome positioning: bringing order to the eukaryotic genome. Trends Cell Biol 22:250-6
Lee, Bum-Kyu; Iyer, Vishwanath R (2012) Genome-wide studies of CCCTC-binding factor (CTCF) and cohesin provide insight into chromatin structure and regulation. J Biol Chem 287:30906-13
Shivaswamy, Sushma; Iyer, Vishwanath R (2008) Stress-dependent dynamics of global chromatin remodeling in yeast: dual role for SWI/SNF in the heat shock stress response. Mol Cell Biol 28:2221-34
Shivaswamy, Sushma; Iyer, Vishwanath R (2007) Genome-wide analysis of chromatin status using tiling microarrays. Methods 41:304-11

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