Transcriptional repression plays a key role in regulation of gene expression in development and in disease processes. To understand conserved regulatory processes in animals, we have determined both the molecular workings and physiological relevance of transcriptional represser proteins that play key roles in Drosophila development. Knirps is a key regulator of the even-skipped gene, acting on separate enhancer elements via a short-range mechanism. We have discovered how Knirps and related repressers function via distinct repression mechanisms, involving the evolutionary conserved CtBP corepressor protein and a histone deacetylase Rpd3, and we have developed novel insights into the design of cis regulatory elements that bind these repressers. We have identified key aspects of a """"""""cisregulatory grammar"""""""" that predicts how represser proteins can function on defined regulatory elements, laying the groundwork for mathematical and bioinformatic analysis of endogenous enhancers. This work will allow us to apply Drosophila-derived information to general analysis of metazoan cis regulatory element design and evolution. 1. We will quantitatively """"""""map"""""""" regulatory surfaces of genes controlled by transcriptional repressors, and use potential function-based mathematical models to predict the regulatory properties of novel enhancers. 2. We will elucidate of mechanisms of short- and long-range repressors using chromatin immunoprecipitation to identify molecular events associated with repression of embryonic reporter genes. 3. We will assess the function of corepressors we discovered associated with the Knirps represser complex, in particular the evolutionary conserved Groucho corepressor, whose role in short-range repression was previously unrecognized. 4. We will identify the physiological significance of conserved residues and splice-variants of the CtBP corepressor, using whole-animal assays to identify the biological significance of the proteins'activities.
These aims combine empirical and modeling efforts to obtain a """"""""bottoms up"""""""" understanding of transcriptional repression. Our long-term goal is to understand molecular activities of transcriptional control proteins and DNA regulatory sequences that are central to gene expression processes important in development and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056976-13
Application #
7749042
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Tompkins, Laurie
Project Start
1998-01-01
Project End
2010-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
13
Fiscal Year
2010
Total Cost
$298,057
Indirect Cost
Name
Michigan State University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Sayal, Rupinder; Dresch, Jacqueline M; Pushel, Irina et al. (2016) Quantitative perturbation-based analysis of gene expression predicts enhancer activity in early Drosophila embryo. Elife 5:
Wei, Yiliang; Gokhale, Rewatee H; Sonnenschein, Anne et al. (2016) Complex cis-regulatory landscape of the insulin receptor gene underlies the broad expression of a central signaling regulator. Development 143:3591-3603
Payankaulam, Sandhya; Yeung, Kelvin; McNeill, Helen et al. (2016) Regulation of cell polarity determinants by the Retinoblastoma tumor suppressor protein. Sci Rep 6:22879
Wei, Yiliang; Mondal, Shamba S; Mouawad, Rima et al. (2015) Genome-Wide Analysis of Drosophila RBf2 Protein Highlights the Diversity of RB Family Targets and Possible Role in Regulation of Ribosome Biosynthesis. G3 (Bethesda) 5:1503-15
Kok, Kurtulus; Ay, Ahmet; Li, Li M et al. (2015) Genome-wide errant targeting by Hairy. Elife 4:
Dresch, Jacqueline M; Thompson, Marc A; Arnosti, David N et al. (2013) TWO-LAYER MATHEMATICAL MODELING OF GENE EXPRESSION: INCORPORATING DNA-LEVEL INFORMATION AND SYSTEM DYNAMICS. SIAM J Appl Math 73:804-826
Suleimenov, Yerzhan; Ay, Ahmet; Samee, Md Abul Hassan et al. (2013) Global parameter estimation for thermodynamic models of transcriptional regulation. Methods 62:99-108
Li, Li M; Arnosti, David N (2011) Long- and short-range transcriptional repressors induce distinct chromatin states on repressed genes. Curr Biol 21:406-12
Sayal, Rupinder; Ryu, Seuk-Min; Arnosti, David N (2011) Optimization of reporter gene architecture for quantitative measurements of gene expression in the Drosophila embryo. Fly (Austin) 5:47-52
Zhang, Yang W; Arnosti, David N (2011) Conserved catalytic and C-terminal regulatory domains of the C-terminal binding protein corepressor fine-tune the transcriptional response in development. Mol Cell Biol 31:375-84

Showing the most recent 10 out of 30 publications