Our Science – Grewal Website

Shiv Grewal, Ph.D.

Laboratory of Biochemistry and Molecular Biology Head, Chromosome Biology Section Senior Investigator National Cancer Institute Building 37, Room 6050 Bethesda, MD 20892 Phone:   301-594-6389 Fax:   301-435-3697 E-Mail:   grewals@mail.nih.gov

Biography

Dr. Grewal began his scientific career at the University of Cambridge, United Kingdom where he held prestigious Cambridge-Nehru scholarship. After obtaining his PhD in 1992, he joined NCI Frederick as a postdoctoral fellow to pursue his interests in the areas of epigenetic control of gene expression and development. In 1998 Dr Grewal joined Cold Spring Harbor Laboratory faculty as an Assistant Professor. He was promoted to Associate Professor position in 2002. In January 2003, he was appointed Senior Investigator at the Laboratory of Molecular Cell Biology, NCI and is head of Chromosome Biology Section. Dr. Grewal has been awarded the Demerec-Kaufmann award in develomental biology, the 1999 Ellison Medical Foundation new scholar award, the Newcomb Cleveland prize by the American Association for Advancement of Science, NIH Directors's award and the NIH Merit award. Recent work by Grewal laboratory showing a connection between RNAi and heterochromatin formation was selected 'Breakthrough of the Year' by Science magazine

Research

Research in our laboratory is focused on the epigenetic control of higher-order chromatin assembly. The dynamic regulation of higher-order chromosome structure governs diverse cellular processes ranging from stable inheritance of gene expression patterns to other aspects of global chromosome structure essential for preserving genomic integrity. Our earlier studies revealed sequence of molecular events leading to the assembly of heterochromatic structures in the fission yeast Schizosaccharomyces pombe. We found that covalent modifications of histone tails by deacetylase and methyltransferase activities act in concert to establish the “histone code” essential for assembly of heterochromatic structures. Moreover, we showed that distinct site-specific histone H3 methylation patterns dictate the organization of chromosomes into discrete structural and functional domains. Histone H3 methylated at lysine 9 is strictly localized to silent heterochromatic regions whereas H3 methylated at lysine 4, only a few amino acids away, is specific to the surrounding active euchromatic regions. We continue to focus on the role of histone modifications and the factors that recognize specific histone modifications patterns (such as a chromodomain protein Swi6 that specifically binds histone H3 methylated at lysine 9) in the assembly of higher-order chromatin structures and have made significant progress in understanding the mechanism of higher-order chromatin assembly.

We also provided evidence showing that RNA interference (RNAi), whereby double-stranded RNAs silence cognate genes, plays a critical role in targeting of heterochromatin complexes to specific locations in the genome. Our recent work has led to discovery of a self-enforcing loop mechanism though which RNAi machinery operates as a stable component of the heterochromatic domains (via tethering of RNAi complexes to heterochromatin marks) to destroy repeat transcripts that escape heterochromatin-mediated transcriptional silencing. In this loop mechanism, the processing of transcripts by RNAi machinery generate small interfering RNAs (siRNAs) that are utilized for further targeting of heterochromatin complexes, so the mechanism continues. In a comprehensive study, we have developed a high-resolution map of the heterochromatin and euchromatin distribution across the entire fission yeast genome. These analyses together with mapping of RNAi components and large scale sequencing of siRNAs associated with an RNAi effector complex involved in heterochromatic silencing have yielded novel insights into the epigenetic profile of this model eukaryotic genome. The link between RNAi and heterochromatin assembly is conserved in higher eukaryotes including mammals and has broad implications for human biology and disease including cancer.

This page was last updated on 6/11/2008.