Affiliations

Chair and Professor, Biological Chemistry

Member, Cell & Developmental Biology GPB Home Area, Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research, Gene Regulation GPB Home Area, I3T Theme, JCCC Gene Regulation Program Area

Faculty, Cellular and Molecular Pathology PhD Program

Chromatin is a highly condensed complex of nucleic acid and basic proteins whose fundamental subunit, the nucleosome, has the same type of design in all eukaryotes. The nucleosome contains ~200 bp of DNA wrapped around an octamer of histones consisting of two copies of each histone H2A, H2B, H3 and H4. All histones are modified by covalent linkage of extra chemical moieties to the free groups of certain amino acids. Examples include acetylation and methylation of lysines, methylation of arginines and phosphorylation of serines. These modifications are transient and able to change the functional properties of the chromatin fiber, thereby affecting all cellular processes that are based on DNA such as transcription. Until recently, most studies of histone modifications have been by-and-large reductionist, focusing on individual promoters. While these studies have revealed important principles, a more comprehensive understanding of chromatin requires that we ascend in scale to genome-wide views to discern biological elements that are not apparent in gene-by-gene surveys. The overall goal of our laboratory is to understand the dynamics, establishment and maintenance mechanisms of histone modifications on a global scale. We use the yeast Saccharomyces cerevisiae as a model organism and combine standard biochemistry, molecular biology, and genetic protocols with high throughput techniques such as DNA microarrays to simultaneously assay histone modifications throughout the genome. Preliminary evidence from our genome-wide studies suggests that we need to develop novel conceptual frameworks for integrating such global knowledge into a predictive model of chromatin biology. We are also interested in applying the lessons learned in yeast to higher eukaryotes. Such transition is straightforward due to the very high degree of conservation of both histone modifications and the relevant enzymes. Using the tools developed in yeast, we have recently shown that combinatorial patterns of histone modification are predictors of clinical outcome in prostate cancer.

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