Judd Rice Assistant Professor Biochemistry & Molecular Biology Zilkha Neurogenetic Institute Keck School of Medicine

Education:
BS 1993 Molecular and Cellular Biology - University of Arizona, Tucson
PhD 2000 Pharmacology and Toxicology - University of Arizona, Tucson

Postdoctoral Research Fellowship:
2000 - 2003 University of Virginia, Charlottesville

Started at USC: 2003

Research Topics: Gene Regulation/Transcription, Cancer Genetics, Cell Cycle, Growth & Proliferation, Protein Chemistry/Enzymology, Epigenetics

Research Description

Each human chromosome contains 50-250 x 106 base pairs of DNA that compacts into an orderly structure by interacting with chromosomal proteins. Together, the DNA and these chromosomal proteins are generically described as chromatin. In eukaryotic organisms, the ability to precisely regulate nuclear processes, such as gene activation, is hindered by the inherently transcriptionally repressive chromatin environment where DNA is tightly packaged with chromosomal proteins. The overall goal of my lab is to elucidate the mechanisms and factors involved in chromatin-mediated events, including transcription. Currently, this is done by studying the post-translational modifications of the N-terminal tails of the histone proteins.

The fundamental structural unit of chromatin is the nucleosome which consists of the core histone octamer (two each of histone proteins H2A, H2B, H3 and H4) and the associated 146 base pairs of DNA that wraps twice around them. While the C-terminus of the histone proteins serve to form the nucleosome, the highly basic N-terminal tails of the histones protrude from the nucleosome and are believed to interact with the negatively charged phosphate backbone of the DNA and with the nuclear environment. Therefore, the tight association of the histone proteins and DNA present a major obstacle to the accessibility of other nuclear proteins, such as transcription factors, and hence directly influences gene expression.

The precise organization of chromatin is critical for many cellular processes including transcription, replication, repair, recombination and chromosome segregation. Recent evidence indicates that dynamic changes in chromatin structure are directly influenced by the post-translational modifications of the N-terminal tails of the histone proteins. Specific amino acids within histone tails are targets for a number of post-translational modifications including acetylation, phosphorylation, poly(ADP-ribosylation), ubiquitination and methylation. These covalent modifications may likely alter the histone tail interaction with DNA or with chromatin-associated proteins that may be required for different downstream cellular processes including gene expression. The best studied of these modifications is the acetylation of histone tails which is intimately associated with transcriptional activation (acetylated histones) or repression (deacetylated histones). Furthermore, the dysfunction of chromatin-modifying proteins are recognized to play important roles in many human pathologies, including cancer, suggesting that these modifications may be potential targets for therapeutic intervention.

We have recently discovered the mammalian enzyme responsible for one of these modifications, the methylation of lysine 20 of histone H4 (H4 Lys20). This enzyme, known as PR-Set7, and the methylation of H4 Lys20 are both essential for survival. Interestingly, we have also discovered that H4 Lys20 methylation is associated with heterochromatin, or transcriptionally inactive regions. In addition, both PR-Set7 and H4 Lys20 methylation increase during mitosis, suggesting that this heterochromatin-associated modification is epigenetically transmitted. My lab will continue to explore the biological relevance of PR-Set7 and H4 Lys20 methylation in mammalian systems. Based on our previous findings, we hypothesize that the cell cycle-regulated control of PR-Set7 and H4 Lys20 methylation is critical to epigenetically maintain proper chromatin structure. Therefore, we predict that perturbation of H4 Lys20 methylation may have drastic cellular consequences such as defects in cell cycle progression, gross alterations in global chromatin and chromosomal structures, increased genomic instability and enhanced oncogenic transformation potential which can all contribute to a cancer phenotype. This hypothesis is currently being tested in human cell lines. Once these findings are validated in vitro, one of my long-term goals will be to create and analyze transgenic mouse models.

One other long term goal of the lab is to develop a high throughput system for the genomic analysis of the various histone modifications. Although these modifications are easily detected in immunofluorescence studies, their precise location within the human genome at any given time is unknown. To determine these locations, we will develop and perform (Chip)2 experiments: chromatin immunoprecipitation (ChIP) using the modification-specific (i.e. acetyl, methyl, phos, etc.) antibodies in human cells followed by hybridization to DNA microarray chips contain partial coverage of the human genome. Once perfected, this process will be streamlined to quickly and confidently investigate alterations in histone modifications at numerous relevant genomic regions during many different types of cellular processes including development, differentiation, tumor progression, the cell cycle, apoptosis, oxidative stress, hypoxia, response to xenobiotics/hormones and many more. For the first time ever, we will be provided with a clear detail of chromatin dynamics within the living cell during these various fundamental biological processes.