Investigator, Director of Postdoctoral Affairs Stowers Institute for Medical Research
Protein Complexes that Modify Chromatin and Regulate Gene Transcription
Eukaryotic chromosomes comprise DNA that is complexed with small basic proteins, histones and other proteins to generate chromatin. The tight association of these proteins with DNA provides a level of transcription control and contributes to epigenetic mechanisms of gene regulation. For example, the amino-terminal tail domains of the core histone proteins are sites of numerous post-translational modifications. In addition to potential effects on chromatin structure, these modifications act as binding sites/receptors for protein complexes that activate or repress gene transcription. Thus, histone modification can be used to generate a "code" of signals on the surface of the chromosome fiber, which provides regulatory information above that contained in the DNA sequence. Our laboratory focuses on studying the protein complexes that carry out these histone modifications and those that recognize the resulting signals.
Our laboratory works with yeast, flies and mammalian cells to identify and study protein complexes that modify chromatin for transcription. Recent research in yeast has resulted in the discovery of the Set2/Rpd3S pathway, by which RNA polymerase II signals through histone methylation for the retention of the original histones on a gene during transcription and the deacetylation of histones in the wake of the polymerase. In flies, we discovered the role of the Tip60 acetyltransferase complex in histone-variant modification and exchange during DNA repair and the novel metazoan ATAC acetyltransferase complex that controls MAP kinase signaling in downstream target genes. Additionally, we found that the highly conserved SAGA complex, originally discovered in yeast in our laboratory, plays an important post-transcription initiation role in tissue-specific gene expression in Drosophila. In human cells, we have discovered novel functions of histone deacetylase inhibitor compounds (which are anti-cancer drugs) and novel subunits of histone deacetylase complexes that control cell migration.