We study the molecular mechanisms by which chromatin-signaling networks effect nuclear and epigenetic programs, and how dysregulation of these pathways leads to cancer and other human diseases. Our work centers on the biology of lysine methylation, a principal chromatin-regulatory mechanism that directs epigenetic processes. We study how lysine methylation events on histone and non-histone proteins are generated, sensed, and transduced, and investigate how these chemical marks integrate with other cellular signaling systems to govern diverse cellular functions important for human health and disease.
A highly complex molecular network at chromatin regulates eukaryotes genomes, with all DNA-templated processes being fundamentally affected by chromatin structure and dynamics. One of the major mechanisms for chromatin regulation involves the reversible covalent post-translational modification of histone proteins by chemical moieties such as acetyl-, methyl- and phospho- groups. These different histone modifications are linked to discrete chromatin states and are thought to regulate the extent of accessibility of DNA to transacting factors. Of the various histone modification systems, histone methylation is the most diverse with respect to the number of residues targeted for modification, potential for signaling, and biological functions regulated.
Histones can be reversibly methylated on the nitrogen side-chain of lysine residues. This process, while subtly changing the primary structure of a peptide, greatly increases the information encoded within the molecule. Lysine residues can accept up to three methyl groups, forming mono-, di-, and trimethylated derivatives, with a unique activity frequently being coupled to the specific extent of methylation on the lysine residue.