Peter W. Lewis

Mechanisms of chromatin assembly, gene silencing, and epigenetic inheritance

My research program aims to understand the mechanisms that underlie silent chromatin (heterochromatin) in animal cells. Heterochromatin is critical for regulating gene expression, maintaining genome integrity, and ensuring proper cellular differentiation.

Our focus extends to two distinct types of heterochromatin: constitutive, which suppresses repetitive regions such as telomeres and transposable elements, and facultative, which dynamically modulates genes involved in cell type specification and cell cycle regulation.

We primarily focus on addressing fundamental mechanisms of establishment and maintenance of heterochromatin, while also exploring how misregulation can promote specific human cancers. Our projects have a dual focus, combining both fundamental research and disease-related inquiries. By integrating these aspects, our objective is a comprehensive understanding of heterochromatin biology and its implications in disease. We use a variety of experimental approaches, including highly purified biochemical assays, proteomic and genomic analysis, and forward genetic screens in mammalian cell lines.

Exploring PRC2 Recruitment and Activity in Development and Disease
The Polycomb Repressive Complex 2 (PRC2) is one component of the two main Polycomb group protein complexes that function in a collaborative crosstalk with K27 methylation on histone H3 (H3K27me3) to initiate and maintain transcriptional silencing. The Polycomb group enzyme complexes, PRC1 and PRC2, work together with H3K27me3 to regulate the spatial and temporal expression patterns of developmentally regulated genes. Misregulation of PRC2 and H3K27me3 can cause developmental defects and specific types of cancer. We seek to define the factors that impact PRC2 recruitment and activity by using a combination of biochemical and genomic approaches.

Defining Chromatin-mediated of Silencing Retrotransposable Elements
Constitutive heterochromatin, characterized by the presence of H3K9me3 and 5-methylcytosine, plays a vital role in safeguarding genome integrity by silencing retrotransposable elements. Our findings have revealed that H3K9me3, the histone variant H3.3 along with its deposition factor ATRX-DAXX, and the Human Silencing Hub (HuSH) complex act in concert to silence retrotransposable elements in mammals. Our research seeks to uncover the biochemical pathways and key factors involved in the establishment of heterochromatin at transposons and other highly repetitive genomic sequences.