: Drosophila presents an ideal model organism for the study of human cis-regulation. Its genome shares the structure and major features of the human genome;all major families of transcription factors, both the basal machinery and site-specific factors;the overall regulatory structure of developmental genes such as the Hox clusters;many of the """"""""master regulatory"""""""" transcription factor proteins such as PAX6/eyeless and Distalless that control organ or tissue identity. In many cases, human proteins function in Drosophila just as well as Drosophila proteins. In addition to the shared biology, the fly also offers powerful experimental tools not yet available for mammalian species. Its small genome size, at 130 Mb, is amenable to genome-wide systematic experimentation at a resolution not yet achievable in the human. Additionally, a total of 12 fully sequenced species provide one of the richest comparative genomic datasets, powerful enough to identify individual functional binding sites of regulators across the entire genome. Finally, the wealth of high throughput experimental techniques enables us to validate functional predictions in vivo. In this proposal, we exploit these unique features to produce a comprehensive cis-regulatory map of the Drosophila genome, using a combined experimental and computational approach. We will identify fly promoter regions, short and long range enhancers, insulator and repressor regions, and their defining characteristics based on cis-regulatory motifs and grammars, chromatin state, and transcription factor binding. This project serves as a pilot for the full-scale mapping of functional regulatory elements in the human genome. The methods and strategies developed will be crucial for informing the human genome. In addition, the body of knowledge gained will be invaluable in the understanding of many human diseases and disorders due to regulatory malfunction of gene regulation. Drosophila is an ideal model system for this project, for its compact genome size, experimental resources, and comparative genomics power, while retaining all the major characteristics of the human genome for the study of gene regulation.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HG004264-04
Application #
7822938
Study Section
Special Emphasis Panel (ZHG1-HGR-P (J1))
Program Officer
Feingold, Elise A
Project Start
2007-05-08
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$2,209,703
Indirect Cost
Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Erclik, Ted; Li, Xin; Courgeon, Maximilien et al. (2017) Integration of temporal and spatial patterning generates neural diversity. Nature 541:365-370
Slattery, Matthew; Ma, Lijia; Spokony, Rebecca F et al. (2014) Diverse patterns of genomic targeting by transcriptional regulators in Drosophila melanogaster. Genome Res 24:1224-35
Boyle, Alan P; Araya, Carlos L; Brdlik, Cathleen et al. (2014) Comparative analysis of regulatory information and circuits across distant species. Nature 512:453-6
Arthur, Robert K; Ma, Lijia; Slattery, Matthew et al. (2014) Evolution of H3K27me3-marked chromatin is linked to gene expression evolution and to patterns of gene duplication and diversification. Genome Res 24:1115-24
Oh, Hyangyee; Slattery, Matthew; Ma, Lijia et al. (2014) Yorkie promotes transcription by recruiting a histone methyltransferase complex. Cell Rep 8:449-59
Hattori, Takamitsu; Taft, Joseph M; Swist, Kalina M et al. (2013) Recombinant antibodies to histone post-translational modifications. Nat Methods 10:992-5
Slattery, Matthew; Voutev, Roumen; Ma, Lijia et al. (2013) Divergent transcriptional regulatory logic at the intersection of tissue growth and developmental patterning. PLoS Genet 9:e1003753
Oh, Hyangyee; Slattery, Matthew; Ma, Lijia et al. (2013) Genome-wide association of Yorkie with chromatin and chromatin-remodeling complexes. Cell Rep 3:309-18
Slattery, Matthew; Negre, Nicolas; White, Kevin P (2012) Interpreting the regulatory genome: the genomics of transcription factor function in Drosophila melanogaster. Brief Funct Genomics 11:336-46
Acharya, Pankaj; Negre, Nicolas; Johnston, John et al. (2012) Evidence for autoregulation and cell signaling pathway regulation from genome-wide binding of the Drosophila retinoblastoma protein. G3 (Bethesda) 2:1459-72

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