Metazoan development requires both intercellular signaling and the integration of these signals within cells to produce a transcriptional response. While many signaling pathways are well characterized, understanding on a global scale the interplay between signal transduction and gene transcription - genetic regulatory networks -remains a major challenge for current genomics research. We have explored in detail part of one such network, which specifies the fate of a subset of Drosophilamuscle and cardiac progenitor cells by the combined action of three signaling pathways, including the Ras pathway via input from both EGF and FGF receptors. The transcription factors downstream of these pathways, and tissue-specific factors induced by them, are integrated at a single transcriptional enhancer for a progenitor identity gene, the even skippedMuscle and Heart Enhancer (MHE). Therecent sequencing of the Drosophilagenome offers an exciting opportunity to extend the insights garnered from our investigation of the MHE on a genome-wide scale. Here, a computational analysis will be used to identify cis-regulatory elements that share features of the MHE and that regulate mesodermal gene expression in a similar spatiotemporal pattern. Invivo techniques, including the analysis of reporter transgenes, will be used to validate the computer predictions. The signaling component of the regulatory networks in which these cisregulatory elements act will be investigated using DNA microarrays. The respective contributions of the FGF and EGF-receptor pathways to Ras-mediated mesodermal signaling, non-Ras-mediated activities of these receptors, and the individual contributions of specific Ras transcriptional effectors will be determined, as will the combined effects of multiple growth factor signals. These approaches will significantly increase our understanding of combinatorial signaling and transcriptional responses by identifying new genes and regulatory elements, and provide insight into the genetic regulatory networks that mediate responses to signaling in a specific regulatory context. The research detailed in this proposal will provide the candidate with an ideal opportunity to apply a strong background in developmental genetics to the emerging fields of computational and functional genomics in a rich learning and research environment, in preparation for an independent academic research career.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Career Transition Award (K22)
Project #
1K22HG002489-01
Application #
6459346
Study Section
Ethical, Legal, Social Implications Review Committee (GNOM)
Program Officer
Feingold, Elise A
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$159,902
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Halfon, Marc S; Zhu, Qianqian; Brennan, Elizabeth R et al. (2011) Erroneous attribution of relevant transcription factor binding sites despite successful prediction of cis-regulatory modules. BMC Genomics 12:578
Leatherbarrow, John R; Halfon, Marc S (2009) Identification of receptor-tyrosine-kinase-signaling target genes reveals receptor-specific activities and pathway branchpoints during Drosophila development. Genetics 181:1335-45
Zhu, Qianqian; Halfon, Marc S (2009) Complex organizational structure of the genome revealed by genome-wide analysis of single and alternative promoters in Drosophila melanogaster. BMC Genomics 10:9
Halfon, Marc S; Gallo, Steven M; Bergman, Casey M (2008) REDfly 2.0: an integrated database of cis-regulatory modules and transcription factor binding sites in Drosophila. Nucleic Acids Res 36:D594-8
Ivan, Andra; Halfon, Marc S; Sinha, Saurabh (2008) Computational discovery of cis-regulatory modules in Drosophila without prior knowledge of motifs. Genome Biol 9:R22
Zhu, Qianqian; Halfon, Marc S (2007) Vector-dependent gene expression driven by insulated P-element reporter vectors. Fly (Austin) 1:55-6
Li, Long; Zhu, Qianqian; He, Xin et al. (2007) Large-scale analysis of transcriptional cis-regulatory modules reveals both common features and distinct subclasses. Genome Biol 8:R101
Estrada, Beatriz; Choe, Sung E; Gisselbrecht, Stephen S et al. (2006) An integrated strategy for analyzing the unique developmental programs of different myoblast subtypes. PLoS Genet 2:e16
Gallo, Steven M; Li, Long; Hu, Zihua et al. (2006) REDfly: a Regulatory Element Database for Drosophila. Bioinformatics 22:381-3
Choe, Sung E; Boutros, Michael; Michelson, Alan M et al. (2005) Preferred analysis methods for Affymetrix GeneChips revealed by a wholly defined control dataset. Genome Biol 6:R16