The project seeks to understand the function of the cis-regulatory sequences that control animal development, using the embryo of the pomace fly Drosophila melanogaster as a model system. Given the importance of gene regulation in virtually every facet of biology, including many human diseases, it is remarkable how poorly we understand the relationship between the base sequence of the genomic regions that control transcription and their function. Despite a growing catalog of well-characterized regulatory sequences from numerous species, especially D. melanogaster, we still can not reliably recognize regulatory sequences in DNA, determine the expression pattern of a gene from the sequences that surround it, predict the consequences of variation in regulatory sequences, or design regulatory sequences de novo to produce a desired pattern of expression. The early D. melanogaster embryo has long been a model for the study of transcriptional regulation. During the first several hours of its development, the D. melanogaster embryo transforms a small number of crude spatial cues left behind by its mother into intricate spatial patterns of expression of thousands of genes that establish the body plan and tissue identities of the embryo, larvae and adult fly. Technological advances in the last decade have enabled the generation of an increasingly detailed portrait of this regulatory network and the molecular events that underlie it, as well as genome sequences of D. melanogaster and many of its genetic variants and sister species. The central premise of this proposal is that we can infer from these data the molecular logic of gene regulation. In particular, we propose to model three aspects of this system: 1) the manner in which regulatory information is distributed across the D. melanogaster genome, 2) constraints on the evolution of regulatory sequences, and 3) the detailed relationship between DNA sequence and gene expression. Each of these models will reveal not only details of the D. melanogaster regulatory network, but will also illuminate the biophysical and logical principles that unite gene regulation in all animals, including humans.

Public Health Relevance

Thanks to remarkable advances in genome sequencing, we will all soon have access to the sequence of our own DNA. But in order to make optimal use of this information, we need to understand the functional consequences of the distinct genetic variants we harbor. This grant uses the fly Drosophila melanogaster as a model to probe the function of those areas of animal genomes that, by regulating when are where genes are active, shape our appearance, physiology, behavior and susceptibility to disease.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project (R01)
Project #
5R01HG002779-11
Application #
8327319
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Feingold, Elise A
Project Start
2003-06-13
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
11
Fiscal Year
2012
Total Cost
$347,599
Indirect Cost
$102,574
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Kuntz, Steven G; Eisen, Michael B (2014) Drosophila embryogenesis scales uniformly across temperature in developmentally diverse species. PLoS Genet 10:e1004293
Paris, Mathilde; Kaplan, Tommy; Li, Xiao Yong et al. (2013) Extensive divergence of transcription factor binding in Drosophila embryos with highly conserved gene expression. PLoS Genet 9:e1003748
Lusk, Richard W; Eisen, Michael B (2013) Spatial promoter recognition signatures may enhance transcription factor specificity in yeast. PLoS One 8:e53778
Shultzaberger, Ryan K; Maerkl, Sebastian J; Kirsch, Jack F et al. (2012) Probing the informational and regulatory plasticity of a transcription factor DNA-binding domain. PLoS Genet 8:e1002614
Kaplan, Tommy; Li, Xiao-Yong; Sabo, Peter J et al. (2011) Quantitative models of the mechanisms that control genome-wide patterns of transcription factor binding during early Drosophila development. PLoS Genet 7:e1001290
Harrison, Melissa M; Li, Xiao-Yong; Kaplan, Tommy et al. (2011) Zelda binding in the early Drosophila melanogaster embryo marks regions subsequently activated at the maternal-to-zygotic transition. PLoS Genet 7:e1002266
Shultzaberger, Ryan K; Malashock, Daniel S; Kirsch, Jack F et al. (2010) The fitness landscapes of cis-acting binding sites in different promoter and environmental contexts. PLoS Genet 6:e1001042
Bradley, Robert K; Li, Xiao-Yong; Trapnell, Cole et al. (2010) Binding site turnover produces pervasive quantitative changes in transcription factor binding between closely related Drosophila species. PLoS Biol 8:e1000343
Li, Jiang; Liu, Zheyun; Tan, Chuang et al. (2010) Dynamics and mechanism of repair of ultraviolet-induced (6-4) photoproduct by photolyase. Nature 466:887-890
Lusk, Richard W; Eisen, Michael B (2010) Evolutionary mirages: selection on binding site composition creates the illusion of conserved grammars in Drosophila enhancers. PLoS Genet 6:e1000829

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