We propose to use newly developed computational and experimental technologies to model how chromatin modifying complexes contribute to transcriptional regulation of the yeast genome. Genome-wide location analysis, a powerful technique that identifies the set of genes that are bound by regulatory proteins in living cells, will be used to identify the portions of the yeast genome where each of the known chromatin modifying complexes are associated. At least one representative subunit of each of the yeast chromatin modifying complexes will be epitope-tagged and the genomic location of the chromatin regulator will be determined. We will combine previously obtained knowledge of the genome-wide location of DNA-binding regulators with new genome-wide location information for chromatin modifying complexes along with expression data to develop a model for the combination of regulators that operate at most genes. As part of this model, we will explore if physically proximate genes are influenced by a single chromatin-modifying complex. We have shown that some chromatin modifying complexes are recruited by DNA-binding transcriptional regulators, and that others are recruited through a component of the general transcription apparatus. We will model how each of the chromatin regulators are recruited to most yeast genes and the temporal scope of their action. We will monitor dynamic changes in chromatin regulators in synchronized cells and build a model of the yeast cell cycle transcriptional regulatory network that incorporates information on both DNA-binding regulators and chromatin modifying complexes. We will test key features of the model using cells with mutations in chromatin modifying complexes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM069676-01
Application #
6708674
Study Section
Genetics Study Section (GEN)
Program Officer
Carter, Anthony D
Project Start
2004-06-01
Project End
2008-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
1
Fiscal Year
2004
Total Cost
$747,351
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Rolfe, P Alexander; Bernstein, Douglas A; Grisafi, Paula et al. (2012) Ruler arrays reveal haploid genomic structural variation. PLoS One 7:e43210
Dowell, Robin D; Ryan, Owen; Jansen, An et al. (2010) Genotype to phenotype: a complex problem. Science 328:469
Wolf, Joshua J; Dowell, Robin D; Mahony, Shaun et al. (2010) Feed-forward regulation of a cell fate determinant by an RNA-binding protein generates asymmetry in yeast. Genetics 185:513-22
Bumgarner, Stacie L; Dowell, Robin D; Grisafi, Paula et al. (2009) Toggle involving cis-interfering noncoding RNAs controls variegated gene expression in yeast. Proc Natl Acad Sci U S A 106:18321-6
Zeitlinger, Julia; Stark, Alexander; Kellis, Manolis et al. (2007) RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo. Nat Genet 39:1512-6
Zeitlinger, Julia; Zinzen, Robert P; Stark, Alexander et al. (2007) Whole-genome ChIP-chip analysis of Dorsal, Twist, and Snail suggests integration of diverse patterning processes in the Drosophila embryo. Genes Dev 21:385-90
Pokholok, Dmitry K; Zeitlinger, Julia; Hannett, Nancy M et al. (2006) Activated signal transduction kinases frequently occupy target genes. Science 313:533-6
Yeang, Chen-Hsiang; Jaakkola, Tommi (2006) Modeling the combinatorial functions of multiple transcription factors. J Comput Biol 13:463-80
Qi, Yuan; Rolfe, Alex; MacIsaac, Kenzie D et al. (2006) High-resolution computational models of genome binding events. Nat Biotechnol 24:963-70
Pokholok, Dmitry K; Harbison, Christopher T; Levine, Stuart et al. (2005) Genome-wide map of nucleosome acetylation and methylation in yeast. Cell 122:517-27

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