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)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM028630-31
Application #
9319292
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Carter, Anthony D
Project Start
1980-12-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2019-07-31
Support Year
31
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Biochemistry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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