Jeffery Simon, PhD

Research Techniques:

Chromatin modification; Chromosome spreads and immunostaining;, Genetics and developmental biology of Drosophila;
Biochemistry of protein-protein interactions and nuclear protein complexes

Research Interests:

Work in the Simon laboratory concerns the molecular mechanisms that control animal development. In order for a multicellular organism to develop properly, specific genes must be turned on or off in specific cells. The lab is studying a set of genes, called homeotic or HOX genes, that control development in the fruit fly, Drosophila. The lab uses a combination of molecular biology, biochemistry, and genetics to study how these genes are regulated in fly embryos. 

A major project concerns how transcription of HOX genes is repressed in specific body regions. At least 10 proteins, termed Polycomb group (PcG) proteins, have been identified that cooperate to provide repression. These proteins regulate transcription by modifying the chromatin organization of target genes. The lab is studying the molecular mechanisms of protein complexes formed by these repressors. One of these repressor complexes, called Polycomb repressive complex 2 (PRC2), has an enzyme activity that methylates a specific lysine residue (K27) of histone H3, a fundamental component of eukaryotic chromatin. The lab is seeking to understand how this repressor complex works, how it is regulated, and how this covalent chromatin modification influences gene expression during development.&

Mice and humans have HOX genes and Polycomb group repressors that resemble their fly counterparts in structure and function. Furthermore, mammalian versions of PcG repressors, including the E(Z) histone methyltransferase which functions in PRC2, have been implicated in stem cell maintenance, X-chromosome inactivation, and in cancers of the breast, prostate, and many other tissues.  A new project in the lab seeks to understand the role of Polycomb group repressors and histone methylation in alterations of breast cancer cells.  By studying PcG repressors in flies and mammalian cells, we expect to gain insight into fundamental aspects of chromatin biology and development, as well as chromatin mechanisms that contribute to disease.

Selected Publications:

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.

 Simon, J.A. and Kingston, R.E. (2009).  Mechanisms of Polycomb gene silencing: knowns and unknowns.  Nature Rev. Mol. Cell Biol. 10: 697-708.

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.

Zhu, C.C., Bornemann, D.J., Zhitomirsky, D., Miller, E.L., O'Connor, M.B. and Simon, J.A. (2008). Drosophilahistone deacetylase-3 controls imaginal disc size through suppression of apoptosis. PLoS Genetics 4(2): e1000009.

Simon, J.A and Lange, C.A. (2008). Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mut. Research 647:21-29.

Wang, L., Jahren, N., Vargas, M.L., Andersen, E.F., Benes, J., Zhang, J., Miller, E.L., Jones, R.S. and Simon, J.A. (2006). Alternative ESC and ESC-Like subunits of a Polycomb group histone methyltransferase complex are differentially deployed during Drosophila development. Mol. Cell. Biol. 26, 2637-2647.

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.

Peterson, A.J., Mallin, D.R., Francis, N.J., Ketel, C.S., Stamm, J., Voeller, R.K., Kingston, R.E. and Simon, J. A. (2004). Requirement for Sex Comb on Midleg protein interactions in Drosophila Polycomb group repression. Genetics 167, 1225-1239.

Simon, J.A. (2003). Polycomb group proteins – Quick Guide. Curr. Biol. 13, R79-80.

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

Simon, J.A. and Tamkun, J.W. (2002). Programming off and on states in chromatin: mechanisms of Polycomb and trithorax group complexes. Curr. Opin. Genet. Dev. 12: 210-218.

Fang, J., Feng, Q., Ketel, C.S., Wang, H., Cao, R., Xia, L., Erdjument-Bromage, H., Tempst, P., Simon, J.A. and Zhang, Y. (2002). Purification and functional characterization of SET8, a nucleosomal histone H4-lysine 20-specific methyltransferase. Curr. Biol. 12: 1086-1099.

Roseman, R., Morgan, K., Mallin, D., Roberson, R., Parnell, T.J., Bornemann, D.J., Simon, J.A. and Geyer, P.K. (2001). Long-range repression by multiple Polycomb group proteins targeted in vivo by fusion to a defined DNA-binding domain. Genetics 158, 291-307.

Ng, J., Hart, C.M., Morgan, K. and Simon, J. A. (2000). A Drosophila ESC-E(Z) protein complex is distinct from other Polycomb group complexes and contains covalently modified ESC. Mol. Cell. Biol. 20, 3069-3078.

Shimell, M.J., Peterson, A.J., Burr, J., Simon, J. and O'Connor, M. (2000). Functional analysis of repressor binding sites in the iab-2 regulatory region of the abdominal-A homeotic gene. Dev. Biol. 218, 38-52.

To view these and other publications visit http://www.ncbi.nlm.nih.gov/PubMed
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