Faculty & Research

Richard S. Jones, Ph.D. Professor Ph.D.: Wesleyan University Postdoctoral training: Harvard University

Office: 333-DLS Tel: 214.768.3810 Fax: 214.768.3955 Email: rjones@smu.edu Lab: 321-DLS Tel: 214.768.2385

Research Interests

Epigenetic Gene Regulation by Polycomb-Group Proteins

Developmental genetics is a field of research concerned with how genes control the process by which a single cell, the fertilized egg, gives rise to an adult organism. Following fertilization, this single cell replicates and divides producing two identical daughter cells. This process is repeated many times, eventually giving rise to all the cells of the body, each containing a complete copy of the genetic information contributed to the fertilized egg by the parents. Along the way, cells begin to exhibit distinguishing characteristics. The specialized characteristics of each cell type is due to the different proteins each is producing. The proteins produced by a cell are determined by which genes are turned on in that cell. Since each cell contains the total complement of genes necessary to make the entire organism, mechanisms must exist by which specific sets of genes are turned on and others are kept off in a given cell type. Since this biological problem is essentially identical in all animals and plants, what is learned from studying one organism is likely to be generally applicable to other organisms. Due to a variety of extremely useful genetic and developmental features, the fruit fly Drosophila melanogaster has become a model system for developmental geneticists.

In eukaryotic cells, the genetic material exists as chromatin in which DNA is wrapped around octamers of the histone proteins H2A, H2B, H3 and H4 to form strings of nucleosomes. Dynamic chromatin processes, including gene expression, are controlled by additional proteins, some of which add or remove covalent modifications to histones, alter the distribution of histone octamers, or modify higher order chromatin packaging. These epigenetic mechanisms regulate the accessibility of specific DNA sites to other nonhistone proteins and/or the abilities of these proteins to affect gene expression once bound.

The Jones lab uses a combination of genetic, immunological and biochemical experimental approaches to study the mechanisms by which products of a class of Drosophila genes, collectively known as the Polycomb-group (PcG), repress the transcription of target genes. We primarily focus on their activities at the best characterized PcG target gene, the Hox gene Ubx. Three major PcG protein complexes have been identified: PRC1, PRC2 and PhoRC. PhoRC is able to bind directly to specific DNA sequences and facilitates recruitment of the other complexes, both of which then modify local chromatin stucture. Using in vitro binding and yeast two-hybrid assays, we have found that the sequence-specific DNA binding PcG protein Pho, a subunit of PhoRC, and a related protein, Pho-like, directly interact with components of the PRC2 complex. E(z), a core subunit of PRC2, is a histone methyltransferase (HMTase) that specifically methylates histone H3 at lysine 27 (H3mK27). The Pc protein, a core subunit of PRC1, contains a chromodomain that preferentially binds to histone H3 tails trimethylated at K27. On the basis of data from chromatin immunoprecipitation (ChIP) assays on wild type and PcG mutant wing imaginal discs and on tissue culture cells in which specific PcG proteins were depleted by RNA interference (RNAi), we have proposed a stepwise assembly pathway for PcG proteins at a target gene: Pho and/or Pho-like directly recruit the PRC2 complex, which methylates H3 at K27, providing a tag that facilitates recruitment of PRC1. In collaboration with Dr. Yi Zhang’s lab (University of North Carolina), we have found that the dRing subunit of PRC1 ubiquitinates histone H2A at K118. We are continuing to use these approaches to examine the distributions of these and other PcG proteins at Ubx, their assembly pathways, and the molecular mechanisms by which they prevent transcription. Overexpression of human PcG homologs contributes to multiple forms of cancer. By defining the activities of PcG proteins in Drosophila, we hope to provide insight into the molecular and biochemical mechanisms underlying the oncogenic activities of their human homologs.

Selected Publications

Lee, N., J. Zhang, R.J. Klose, H. Erdjument-Bromage, P. Tempst, R.S. Jones, and Y. Zhang (2007) The trithorax-group protein Lid is a histone H3 trimethyl-Lys4 demethylase. Nat. Struct. Mol. Biol. 14:341-343.

Wang, J., N. Jahren, M.L. Vargas, E.F. Andersen, J. Benes, J. Zhang, E.L. Miller, R.S. Jones, and J.A. Simon (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.

Wang, H., L. Wang, H. Erdjument-Bromage, M. Vidal, P. Tempst, R.S. Jones, and Y. Zhang (2004) Role of histone H2A ubiquitination in Polycomb silencing. Nature 431:873-878.

Wang, L., J.L. Brown, R. Cao, Y. Zhang, J.A. Kassis, and R.S. Jones (2004) Hierarchical recruitment of Polycomb-group silencing complexes. Molec. Cell 14:637-646.

Sedkov, Y., E. Cho, S. Petruk, L. Cherbas, S.T. Smith, R.S. Jones, P. Cherbas, E. Canaani, J.B. Jaynes, and A. Mazo (2003) Methylation at lysine 4 of histone H3 in ecdysone-dependent development of Drosophila. Nature 426: 78-83.

Cao, R., L. Wang, H. Wang, L. Xia, H. Erdjument-Bromage, P. Tempst, R.S. Jones, and Y. Zhang (2002) Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298:1039-1043.

Wang, L., L. Ding, C.A. Jones, and R.S. Jones (2002) The Drosophila Enhancer of zeste protein directly interacts with dSAP18. Gene 285:119-125.

O’Connell, S., L. Wang, S. Roberts, C.A. Jones, R. Saint, and R.S. Jones (2001) Polycomblike PHD fingers mediate conserved interaction with Enhancer of zeste protein. J. Biol. Chem 276: 43065-43073.

I. Bajusz, L. Sipos, Z. Györgypál, E.A. Carrington, R.S. Jones, J. Gausz, H. Gyurkovics (2001) The Trithorax-mimic allele of Enhancer of zeste renders active domains of target genes accessible to Polycomb-group dependent silencing in Drosophila melanogaster. Genetics 159: 1135-1150.

Sedkov, Y., J.J. Benes, J.R. Berger, K.M. Riker, S. Tillib, R.S. Jones, A. Mazo (1999) Molecular genetic analysis of the Drosophila trithorax-related gene which encodes a novel SET domain protein. Mech. Dev. 82:171-179.

Jones, CA, J. Ng, A.J. Peterson, K. Morgan, J. Simon and R.S. Jones (1998) The Drosophila esc and E(z) proteins are direct partners in Polycomb-group mediated repression. Mol. Cell Biol. 18:2825-2834.

Carrington, E.A and R.S. Jones (1996) The Drosophila Enhancer of zeste gene encodes a chromosomal protein: examination of wild type and mutant protein distribution. Development 122:4073-4083.

Support

NIH, R01-GM046567, Polycomb-group genes and gene regulation, Role PI