Peter Lewis

Our research seeks to define the biochemical mechanisms involved in the establishment and maintenance of silent chromatin, also known as heterochromatin. Our experimental approaches span the spectrum from highly purified biochemical assays to proteomic and genomic analyses, and genetic screens.

Covalent modifications to DNA and histone proteins allows chromatin to act as a dynamic information hub that integrates diverse biochemical stimuli to regulate genomic DNA access for transcription. To preserve cell identity, lineage-specific gene expression must be maintained, and failure to silence genes from other lineages has the potential to cause developmental defects or promote tumorigenesis.

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. 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.

Heterochromatin containing H3K9me3 and 5-methylcytosine plays an important role in maintaining genome integrity by silencing transposable elements.  We found that H3K9me3, the histone variant H3.3 and its deposition factor ATRX-DAXX, and the Human Silencing Hub (HuSH) complex function together to silence retrotransposable elements in mammals. Our research seeks to define the pathways and factors involved in establishing 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