The information content of every human cell is not only encoded in the genomic DNA sequence, but within histone proteins that together form chromatin. Chromatin is a highly dynamic system, which is constantly restructuring in response to developmental and environmental cues. The basic subunit of chromatin is called the nucleosome, and each nucleosome is encoded with information that dictates localized DNA-templated processes. This information is largely encoded by post-translational modifications (PTMs) on the histones. One of the most important questions in biology is how this information is read out and regulated in response to development and the environment. A major role of histone PTMs is to guide the action of chromatin associated proteins, that work together to mediate changes in chromatin structure. Chromatin associated proteins (CAPs) read out the histone modification signature through the combinatorial action of protein subdomains called histone reader domains. Much is known about how individual reader domains associate with isolated histone fragments. However, almost nothing is known about how histone PTMs are read out in the physiologically relevant context of the nucleosome.
The goal of the Musselman laboratory is to determine the molecular basis of how reader domains interpret the information encoded in histones in a chromatin relevant context, and how readers work together to enable a regulatory complex to decipher and respond to a dynamic chromatin landscape. We are pioneering the use of nuclear magnetic resonance (NMR) spectroscopy, combined with other biochemical and biophysical methods, to examine modified nucleosomes and the structural and thermodynamic basis of association of reader domains. We have found that the nucleosome context is indeed critical for understanding the function of histone modifications and reader domains.