We are interested in understanding chromatin’s contribution to mammalian gene expression in both normal cells and in cancer cells.
A human cell contains about two meters of DNA that must be accommodated by its tiny nucleus. This presents a phenomenal packaging problem, which nature has solved by tightly wrapping the DNA into chromatin. Chromatin’s operational structure is the nucleosome, consisting of 146 bp of DNA wrapped around a bundle of eight core histone proteins (H3, H4, H2A and H2B). The packing of nucleosomes into increasingly complex structures explains how the DNA fits. When genes are expressed, the chromatin template must alter its structure, unpacking itself to make those genes accessible to the scores of proteins involved in transcription. Epigenetics is the study of this process and is defined as the collective alterations to the chromatin template that produce and propagate different patterns of gene expression and silencing from the same genome (Allis et al. 2007. Epigenetics. Cold Spring Harbor: CSHL Press.)
Alterations to the chromatin template are dynamic and include the activities of ATP-dependent complexes, as well as covalent modification of histones and DNA. A number of covalent modifications to the nucleosome, mostly in histone N-terminal tails, have been described, including methylation, acetylation, phosphorylation and ubiquitination. These covalent modifications define the functional state of chromatin via both cis and trans mechanisms. Cis mechanisms, best typified by acetylation/deacetylation, result in changes to nucleosome packing that increase or decrease DNA accessibility for transcription. In trans mechanisms, non-histone proteins possessing particular binding domains recognize specific histone modifications and recruit additional factors that regulate transcription. Together cis and trans mechanisms embellish the chromatin fiber to generate biological effects that extend beyond the DNA sequence alone.
Cancer is a disease in which certain genes alter their expression and it is becoming increasingly clear that epigenetics, or chromatin remodeling, plays a critical role in this process. Our research seeks to understand chromatin remodeling and its role in cancer progression. See the PROJECT links for details about our current research.