Harvard Medical School
Department of Biological Chemistry and Molecular Pharmacology (BCMP)
240 Longwood Ave., Building C2, Rooms 315-325
Boston, MA 02115

The molecular mechanisms of transcriptional regulation are highly conserved among eukaryotes. Transcriptional regulation in response to environmental and developmental cues is mediated by the combinatorial and synergistic action of specific DNA-binding activators and repressors on components of the general transcription machinery and chromatin modifying activities. 

Much of the work in this laboratory combines genetic, molecular, and genomic approaches available in yeast to address fundamental questions about transcriptional regulatory mechanisms in living cells. Current projects include 1) genetic experiments to test our three step model for nucleosome positioning; 2) a systematic analysis of general transcription factors involved in initiation using the anchor-away system; 3) a study of factors involved in elongation and nucleosome depletion at 3’ ends; 4) using direct RNA sequencing, a genome wide analysis of mRNA half-life and 3’-end formation, 5) the use of a functional evolutionary approach to understand the roles of various transcripts as well as specific components of transcriptional co-activator and co-repressor complexes and activator and repressor binding sites mediating environmental responses. 

The transcriptional regulatory circuits involved in cellular transformation are of fundamental importance and of course directly relevant to cancer.  We are using two isogenic models (breast cells and fibroblasts) of human cancer to elucidate the transcriptional regulatory circuitry involved in the process of cellular transformation.  This involves mechanistic experiments on the inflammatory feedback loop and related aspects of the cellular transformation process; whole-genome profiles of mRNAs, microRNAs, and transcription factor binding sites to provide an integrated view of cellular transformation; and identifying genes, microRNAs, and regulatory pathways involved in generating cancer stem cells and mammospheres.  Projects include 1) mRNA, miRNA and linc RNA profiling of spheres vs. cancer cells in different types of cancer cells; 2) ribosome profiling during cellular transformation; and 3) large scale ChIP-Seq experiments to determine the role of transcription factors in transformation.  Lastly, having discovered that the diabetes drug metformin selectively kills cancer stem cells, we are investigating the mechanism of metformin action and its potential for prevention and treatment of cancer.