Deciphering the Nucleosome Interactome
Despite every cell in the human body having a nearly identical genetic sequence, divergent patterns of gene expression lead to the development of diverse cell types and functions. These patterns are established through epigenetic changes to the composition and structure of chromatin, the physiologic state of the genome. The repeating unit of chromatin is the nucleosome, in which segments of genomic DNA are wrapped around molecular spools of proteins. By displaying diverse combinations chemical modifications, the nucleosome serves as an active signaling hub in the regulation of genome-templated processes. These processes, including gene expression, DNA replication and DNA damage repair, play fundamental roles in cell development and maintenance of genomic integrity. As such, inappropriate regulation of the epigenetic enzymes that write, read and erase these chemical modifications is correlated with many human diseases, especially cancer.
Yet, we know relatively little with regard to how these epigenetic enzymes recognize and function on their nucleosome targets. We will use protein chemistry to reconstitute ‘designer’ nucleosomes and chromatin, containing defined patterns of post-translational modifications with atomic precision. When paired with structural biology, including X-ray crystallography and single particle cryo-EM, this will allow us to interrogate mechanisms governing specific epigenetic signaling pathways by visualizing them in action at atomic resolution. We will also use proteomics to decipher general patterns of nucleosome recognition in genomic processes. By shedding light on the nucleosome and its function in normal genomic processes, we will gain insight into the many human diseases caused by misregulation of this fundamental signaling system.