The bithorax complex in the fruit fly, Drosophila melanogaster, is a cluster of genes that determines the identities the body segments of the fly. It includes multiple regulatory regions, one for each body segment, which are arranged on the chromosome in the order of the segments that they affect. The genes, and their chromosomal order, are conserved between flies and humans. We wish to understand how the regulatory regions become appropriately activated or repressed in each body segment. The repressed state is imposed by a several genes collectively called the Polycomb Group;these genes are also well conserved. In both flies and mammals, they regulate a large number of other genes required in specific cell types. We are able to isolate nuclei from individual segments of the fly embryo, and map chromosomal proteins across the bithorax complex in each segment. We focus on the Polycomb Group proteins, and on modifications to the histone proteins covering the DNA. We will introduce mutations in critical DNA elements, to learn how large domains of Polycomb-mediated repression are established and maintained.

Public Health Relevance

The human homologs of the Drosophila segment-identity genes are mutated in patients with congenital heart abnormalities, polydactyly, and leukemia. The human homologs of the fly Polycomb Group proteins are required for the regulation of many loci, and one such homolog is misexpressed in multiple human cancers. The molecular mechanisms used by the fly genes should apply to their human counterparts, and so these studies should contribute to our understanding of human development and disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01GM028630-28A1
Application #
8758522
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Carter, Anthony D
Project Start
Project End
Budget Start
Budget End
Support Year
28
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Bowman, Sarah K; Deaton, Aimee M; Domingues, Heber et al. (2014) H3K27 modifications define segmental regulatory domains in the Drosophila bithorax complex. Elife 3:e02833
Bender, Welcome; Lucas, Maura (2013) The border between the ultrabithorax and abdominal-A regulatory domains in the drosophila bithorax complex. Genetics 193:1135-47
Ho, Margaret C W; Johnsen, Holly; Goetz, Sara E et al. (2009) Functional evolution of cis-regulatory modules at a homeotic gene in Drosophila. PLoS Genet 5:e1000709
Peifer, M; Bender, W (1988) Sequences of the gypsy transposon of Drosophila necessary for its effects on adjacent genes. Proc Natl Acad Sci U S A 85:9650-4