Molecular studies of chromatin structure and epigenetics

In the eukaryotic nucleus genomic DNA is hierarchically packaged by histone proteins into chromatin. The fundamental repeating unit of chromatin is the nucleosome, which is comprised of ~146 base pairs of DNA wrapped around an octamer of histones. Gene silencing factors such as Polycomb Repressive Complexes (PRC), the Silent Information Regulator (SIR) complex or Heterochromatin Protein 1 (HP1) specifically bind and organize nucleosomes to form higher-order, compacted chromatin structure. Epigenetic modifications of histones are known to regulate binding of these factors. Compaction of chromatin has been proposed to cause gene repression by creating a block to transcription processes. This compaction is crucial for establishment, maintenance and propagation of distinct patterns of gene expression. In higher eukaryotes, defective gene silencing can result in developmental defects, cellular transformation and malignant outgrowth.

Understanding how chromatin structure and genome architecture regulate gene expression is one of the most important, unexplained frontiers in biology. The goal of our laboratory is to understand the organization and dynamics of chromatin complexes important for the regulation of gene expression both at the genetic and epigenetic levels. We use a combination of structural approaches, including x-ray crystallography and electron microscopy, coupled with biophysical and biochemical experimentation to study mechanisms by which gene silencing complexes impact chromatin structure and repress transcription.

Molecular details of these complexes will be pivotal to understanding their biological function in both normal and disease states and will be central to the development of novel epigenetics-based therapeutics.