How do regulatory sequences control the patterns of gene expression?
Whole genome sequence for a wide variety of organisms has shown us that across taxa, the set of protein coding genes is remarkably similar. How is this common genetic toolkit deployed in new configurations to generate organismal diversity? The evolutionary importance of changes in gene regulation during development is now clear, and a handful of examples have successfully traced the path from distinct phenotypes, to changes in gene expression, and finally to specific changes in genomic regulatory sequence. Yet we lack general principles describing how regulatory sequence relates to its output as gene expression patterns in space and time, severely limiting our understanding of how these sequences are functionally constrained during evolution.
Gene expression in metazoans is controlled by the interaction among cis-regulatory elements (sometimes called enhancers), silencers, insulators, chromatin structure and core promoters. The vast majority of gene specific spatial and temporal information is contained in cis-regulatory elements, which are collections of binding sites for sequence specific DNA-binding transcription factors. Our current work is focused on two parallel questions. First, how do collections of transcription factor binding sites integrate information to produce gene expression patterns? And second, how do cis-regulatory elements and their associated expression patterns evolve?
We focus on the early development of multiple Drosophila species, and integrate a wide variety of experimental and computational approaches. The early development of Drosophila melanogaster is directed by an extremely well characterized transcriptional network, giving us a large number of known transcription factors and regulatory elements to work with. Twelve Drosophila species have recently been sequenced, and more genomic resources are on the way. The relatively simple geometry of the early embryo has allowed us to develop quantitative imaging techniques that yield gene expression information for every cell in the entire embryo over time. Together, these resources give us the opportunity to bring a quantitative system-wide approach to evolutionary developmental biology.
About Angela: Angela received her B.S. in Molecular Biophysics and Biochemistry from Yale University, and her Ph.D. in Biochemistry from the University of California, San Francisco where she studied with Jonathan Weissman. She conducted her postdoctoral work at the University of California Berkeley with Michael Eisen.
Please feel free to contact me about opportunities to join or collaborate with the lab.
Harvard Medical School
Department of Systems Biology
200 Longwood Avenue
Warren Alpert Building