Robert McGinty, M.D., Ph.D.

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 histone proteins. By displaying diverse combinations of histone post-translational 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 modifications is correlated with many human diseases, especially cancer.

Over the past two decades, structural and biochemical studies using peptide fragments of histone proteins have elucidated many mechanisms through which epigenetic enzymes recognize histone sequences and modification patterns. However, these peptide-based approaches preclude a fundamental understanding of how epigenetic signals are integrated within more physiologic states of chromatin.

McGinty Laboratory studies mechanisms governing epigenetic signaling at the nucleosome and chromatin levels. We use protein chemistry to reconstitute ‘designer’ nucleosomes and chromatin, containing defined patterns of post-translational modifications. When paired with structural biology, including X-ray crystallography and single particle cryo-EM, this allows us to interrogate mechanisms governing specific epigenetic signaling pathways at atomic resolution. Together with the Center for Integrative Chemical Biology and Drug Discovery, my lab will leverage our structural studies toward the design of small molecules to disrupt chromatin signaling pathways for basic research and therapeutic goals.

• Deciphering the nucleosome interactome
• Deciphering the nucleosome interactome
• Molecular Mechanisms of Chromatin Recognition