Peter Lewis

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.

Representative Publications:

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Jain SU, Rashoff AQ, Krabbenhoft SD, Hoelper D, Do TJ, Gibson TJ, Lundgren SM, Bondra ER, Deshmukh S, Harutyunyan AS, Juretic N, Jabado N, Harrison MM, Lewis PW. H3 K27M and EZHIP impede H3K27-methylation spreading by inhibiting allosterically stimulated PRC2. Molecular Cell, 2020 Nov 19;80(4):726-735

Jain SU, Khazaei S, Marchione DM, Lundgren SM, Wang X, Weinberg DN, Deshmukh S, Juretic N, Lu C, Allis CD, Garcia BA, Jabado N, Lewis PW. Histone H3.3 G34 mutations promote aberrant PRC2 activity to drive tumor progression. Proc Natl Acad Sci, 2020 Nov 3;117(44):27354-27364

Jain SU, Do TJ, Lund PJ, Cieslik M, Diehl KL, Rashoff AQ, Bajic A, Juretic N, Deshmukh S, Venneti S, Muir TW, Garcia BA, Jabado N, Lewis PW. PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism. Nature Communications, 2019 May 13;(10):2146

Hoelper D, Huang H, Jain A, Patel DJ, Lewis PW. Structural and mechanistic insights into ATRX-dependent and –independent functions of the histone chaperone DAXX. Nature Communications, 2017 Oct 30;8(1):1193

Jayaram H, Hoelper D, Jain SU, Canton N, Lundgren SM, Poy F, Allis CD, Cummings R, Bellon S, Lewis PW. S-adenosyl methionine is necessary for inhibition of the methyltransferase G9a by lysine-9-to-methionine mutation on histone H3. Proc Natl Acad Sci., 2016 May 31;113(22):6182-7

Lu C, Jain SU, Hoelper D, Bechet D, Molden RC, Ran L, Murphy D, Venneti S, Hameed M, Pawel BR, Wunder JS, Dickson BC, Lundgren SM, Jani KS, DeJay N, Papillon S, Andrulis IL, Sawyer SL, Grynspan D, Turcotte RE, Nadaf J, Fahiminiyah S, Muir TW, Majewski J, Thompson CB, Chi P, Garcia BA, Allis CD, Jabado N, Lewis PW. Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science, 2016 May 13;352(6287):844-9