Our long-term goal is to reveal chromatin mechanisms that control gene expression during development and disease. We study the Polycomb group (PcG) transcriptional repressors, one of the premier models for investigating chromatin regulation. Our main focus is Polycomb repressive complex 2 (PRC2), an enzyme that methylates histone H3 on lysine 27 (K27). PRC2 is a fundamental chromatin-modifying machine, conserved in single-celled organisms, plants, and animals to implement gene silencing. The PRC2 output, tri-methylated H3-K27 (H3-K27me3), is a hallmark of repressed chromatin. We were one of several groups that purified PRC2, defined its composition, and revealed K27 specificity. We continue to pursue PRC2 mechanisms and H3-K27me3 consequences using in vitro biochemical assays and in vivo approaches in Drosophila; the conserved machinery yields confidence that mechanistic findings apply broadly to human biology.
Among its many biological roles, PRC2 functions prominently in the transcriptional circuitry that controls embryonic stem cells and it is a central regulator in adult stem cells, such as in skin, muscle and blood. PRC2 is also emerging as a key factor in oncogenesis; PRC2 subunits are overabundant in many types of cancer and PRC2 hyperactivity is a driver in certain leukemias. Direct chemical inhibitors of PRC2, described by several groups in recent years, show promising anticancer effects in cell and animal models. Thus, PRC2 is a druggable target with significant therapeutic potential. Our PRC2 studies contribute to basic understanding of chromatin biology and help to inform strategies for modulating its gene repressive activity in diverse cellular contexts.
Selected Publications (Pubmed Search)
Herzog, V.A., Lempradl, A., Trupke, J., Okulski, H., Altmutter, C., Ruge, F., Boidol, B., Kubicek, S., Schmauss, G., Aumayr, K., Ruf, M., Pospisilik, A., Dimond, A., Senergin, H.B., Vargas, M.L., Simon, J.A., Ringrose, L. (2014). A strand-specific switch in noncoding transcription switches the function of a Polycomb/Trithorax response element. Nature Genet. 46, 973-981.
Rai, A.N., Vargas, M.L., Wang, L., Andersen, E.F., Miller, E.L. and Simon, J.A. (2013). Elements of the Polycomb repressor SU(Z)12 needed for histone H3-K27 methylation, the interface with E(Z), and in vivo function. Mol. Cell. Biol. 33, 4844-4856.
Simon, J.A. and Kingston, R.E. (2013). Occupying chromatin: Polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put. Mol. Cell., 49, 808-824.
Chen, S., Bohrer, L.R., Rai, A.N., Pan, Y., Gan, L., Zhou, X., Bagchi, A., Simon, J.A. and Huang, H. (2010). Cyclin-dependent kinases regulate epigenetic gene silencing through phosphorylation of EZH2. Nature Cell Biol. 12, 1108-1114.
Wang, L., Jahren, N., Miller, E.L., Ketel, C.S., Mallin, D.R. and Simon, J.A. (2010). Comparative analysis of chromatin binding by Sex Comb on Midleg (SCM) and other Polycomb group repressors at a Drosophila Hox gene. Mol. Cell. Biol. 30, 2584-2593.
Joshi, P., Carrington, E.A., Ketel, C.S., Miller, E.L., Jones, R.S. and Simon, J.A. (2008). Dominant alleles identify SET domain residues required for histone methyltransferase of Polycomb repressive complex 2. J. Biol. Chem. 283: 27757-27766.
Ketel, C.S., Andersen, E.F., Vargas, M.L., Suh, J., Strome, S. and Simon, J.A. (2005). Subunit contributions to histone methyltransferase activities of fly and worm Polycomb group complexes. Mol. Cell. Biol. 25, 6857-6868.
Muller, J., Hart, C.M., Francis, N.J., Vargas, M.L., Sengupta, A., Wild, B., Miller, E.L., O'Connor, M.B., Kingston, R.E. and Simon, J.A. (2002). Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 111, 197-208.