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 147 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 reversible and able to change the functional properties of the chromatin fiber, thereby affecting all cellular processes that are based on DNA such as transcription.

The overall goal of our laboratory is to understand the dynamics, establishment and maintenance mechanisms of histone modifications. We use the model organism, Saccharomyces cerevisiae, to understand the basic biology of histone modifications and apply the learned lessons to higher eukaryotes including murine embryonic stem cells, cancer cell lines, and primary human cancer tissues.

We use the budding yeast Saccharomyces cerevisiae as a model organism and combine standard molecular biology approaches with high throughput techniques such as DNA microarrays to simultaneously assay multiple histone modifications throughout the genome. Evidence from our genomewide studies suggests that there are global principles that govern the levels of acetylation of various residues in histones, generating combinatorial patterns of histone modifications. The histone acetylation patterns can define groups of biologically related genes in an unbiased fashion, indicating the feasibility of developing a predictive model of chromatin biology. We also exploit the powerful genetic tools in yeast to dissect the regulatory pathways that control the activity and specificity of histone modifying enzymes for histone subtypes and their modified residues.

Cancer is a disease of genetic and epigenetic alterations. Epigenetics include the interrelated processes of DNA methylation, genomic imprinting and histone modifications. Up until recently, cancer epigenetics has been by and large focused on DNA methylation. However, aberrations in histone modifications are also being increasingly identified in human cancer. These aberrations may occur locally at promoters by inappropriate targeting of histone modifying enzymes, leading to improper expression or repression of individual genes that play important roles in tumorigenesis. In addition to gene-gene differences, we have shown that histone modifications also show aberrations at the levels of whole nuclei, generating cell-cell differences in a given tissue. Importantly, this cellular heterogeneity in total levels of specific histone modifications occur in a stereotypical pattern which can be used to predict prognosis. Our work indicate for the first time that cellular epigenetic heterogeneity may underlie the varied clinical behavior of cancer patients and can be used to predict cancer prognosis.