Peter Lewis, PhD
Position title: Associate Professor, Department of Biomolecular Chemistry
1135, Peter Lewis Biochemistry Building
420 Henry Mall
Madison, WI 53706
My research program is rooted in the idea that eukaryotic chromatin, the physiologically relevant form of genomes, contains an indexing system that represents a fundamental regulatory mechanism. Covalent modifications to both DNA and histone proteins allow chromatin to act as a dynamic information hub that integrates diverse biochemical stimuli to regulate genomic DNA access and ultimately establish and maintain cellular identity. Aberrant chromatin regulation, as a consequence of mutation or abnormal signaling is associated with many diseases, especially cancer. The identification of oncogenic mutations has led to the emerging view of “driver mutations” in chromatin regulators underlying many human cancers. My research is aimed at defining how changes in chromatin structure aid in the establishment and maintenance of gene expression programs involved in normal development and tumorigenesis.
Tumors of the brain and central nervous system are the leading cause of solid tumor-related death in children. Diffuse midline gliomas are driven by a recurrent Lysine-27-Methionine (K27M) missense mutation in histone H3, and posterior fossa ependymomas are driven by aberrant expression of EZHIP. My group discovered that the K27M histone and EZHIP are potent competitive inhibitors of H3K27 methylation by the gene silencing PRC2 methyltransferase enzyme.
How these genetic alterations promote tumorigenesis is poorly understood, and we seek to elucidate the mechanisms by which K27M and EZHIP misregulate PRC2 to promote tumorigenesis by employing a multi-disciplinary approach that integrates molecular, genomic, and pharmacologic methods.
- 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