The Hox genes encode a conserved family of homeodomain-containing transcriptional regulators that are critical for many aspects of animal development, in all metazoans. The long-term goal of this project is to understand how these proteins function as transcriptional regulators at a mechanistic level. Three approaches will be used: 1) a structure-function analysis of three Hox proteins, using an in vivo, rescue-based strategy, focusing especially on Hox protein motifs that interact with Hox cofactors in a context-dependent manner, 2) the high-resolution characterization of individual Hox- targeted regulatory elements, and 3) an analysis of the Hox-dependent chromatin architectures in the imaginal discs, the precursors of the adult fly. Together, these studies will provide important insights int how these and other transcriptional regulators carry out their specific functions during animal development.

Public Health Relevance

This project will investigate the mechanism by which the Hox family of transcriptional regulators controls their downstream target genes in Drosophila. Emphasis is placed on using rescuing transgenes to carry out a structure-function analysis of conserved protein motifs as well as on mechanistic studies of individual, Hox-regulated elements. An analysis of Hox-dependent tissue-specific chromatin structures will also be executed.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM054510-21
Application #
8448113
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
1992-08-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
21
Fiscal Year
2013
Total Cost
$348,793
Indirect Cost
$128,056
Name
Columbia University (N.Y.)
Department
Biochemistry
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Agelopoulos, Marios; McKay, Daniel J; Mann, Richard S (2014) cgChIP: a cell type- and gene-specific method for chromatin analysis. Methods Mol Biol 1196:291-306
Riley, Todd R; Slattery, Matthew; Abe, Namiko et al. (2014) SELEX-seq: a method for characterizing the complete repertoire of binding site preferences for transcription factor complexes. Methods Mol Biol 1196:255-78
Shazman, Shula; Lee, Hunjoong; Socol, Yakov et al. (2014) OnTheFly: a database of Drosophila melanogaster transcription factors and their binding sites. Nucleic Acids Res 42:D167-71
Oh, Hyangyee; Slattery, Matthew; Ma, Lijia et al. (2014) Yorkie promotes transcription by recruiting a histone methyltransferase complex. Cell Rep 8:449-59
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
Agelopoulos, Marios; McKay, Daniel J; Mann, Richard S (2012) Developmental regulation of chromatin conformation by Hox proteins in Drosophila. Cell Rep 1:350-9
Lelli, Katherine M; Noro, Barbara; Mann, Richard S (2011) Variable motif utilization in homeotic selector (Hox)-cofactor complex formation controls specificity. Proc Natl Acad Sci U S A 108:21122-7
Noro, Barbara; Lelli, Katherine; Sun, Liping et al. (2011) Competition for cofactor-dependent DNA binding underlies Hox phenotypic suppression. Genes Dev 25:2327-32
Slattery, Matthew; Ma, Lijia; Negre, Nicolas et al. (2011) Genome-wide tissue-specific occupancy of the Hox protein Ultrabithorax and Hox cofactor Homothorax in Drosophila. PLoS One 6:e14686
Slattery, Matthew; Riley, Todd; Liu, Peng et al. (2011) Cofactor binding evokes latent differences in DNA binding specificity between Hox proteins. Cell 147:1270-82

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