Peter W. Lewis

Biochemical mechanisms of chromatin regulation, genome stability, and cancer

My laboratory investigates the molecular mechanisms that establish and maintain chromatin states and how disruption of these mechanisms alters gene expression, cell identity, and genome stability in cancer. Diffuse midline gliomas and sarcomas provide tractable models for determining how heterochromatin-associated proteins, histone modifications, and chromatin assembly pathways regulate differentiation and cellular state. Our studies connect fundamental chromatin biochemistry with disease-associated changes in genome regulation.

A major focus is Polycomb Repressive Complex 2 (PRC2), a multisubunit histone lysine methyltransferase complex that catalyzes methylation at lysine 27 of histone H3 and generates H3K27me3, a modification associated with transcriptional repression. We ask how PRC2 recognizes chromatin substrates, how interactions with nucleosomes and regulatory factors govern catalytic activity, and how PRC2-dependent chromatin states shape transcriptional programs. These questions provide opportunities to study enzyme regulation, biomolecular recognition, multisubunit protein complexes, and the relationship between molecular activity and cellular phenotype.

We also investigate chromatin-mediated silencing of repetitive genomic elements, including retrotransposons. This work examines how histone variants and chromatin assembly factors cooperate to recognize repetitive sequences, organize repressive chromatin, and preserve genome stability. Retrotransposons and their silencing by cellular machinery provide a powerful system for studying nucleosome assembly, interactions between RNA and chromatin, and the molecular links among chromatin disruption, and innate immune signaling.

To address these questions, we combine biochemical reconstitution and mechanistic assays with proteomic and genomic analyses, genetic screens, and small-molecule perturbations in mammalian cells and cancer models. Most projects in the lab lie at the intersection of biomolecular interactions, chemical biology and enzymology, gene expression and RNA biology, and genome maintenance, with the goal of connecting mechanistic insights from purified molecular systems to cellular phenotypes.