Shiv Grewal has uncovered groundbreaking insights into heterochromatin assembly (compact form of chromatin) and epigenetic control of genome expression using fission yeast Schizosaccharomyces pombe as a model system. He has discovered fundamental mechanisms that target heterochromatin to repetitive elements and other locations throughout the genome. In particular, his discovery of the role of RNAi in heterochromatin formation was cited as “Breakthrough of the Year” (Science, 2002). He further described the role of heterochromatin in controlling diverse regulatory functions that guide 3D genome organization, structure, and stability.
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 that is 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.
Selected Recent Publications
SNF2 Family Protein Fft3 Suppresses Nucleosome Turnover to Promote Epigenetic Inheritance and Proper Replication.Mol Cell. 66(1): 50-62, 2017. [ Journal Article ]
- Nature. 543(7643): 126-130, 2017. [ Journal Article ]
- Nature. 516: 432-435, 2014. [ Journal Article ]
Mtr4-like protein coordinates nuclear RNA processing for heterochromatin assembly and for telomere maintenance.Cell. 155: 1061-74, 2013. [ Journal Article ]
- Nature. 493: 557-60, 2013. [ Journal Article ]
Dr. Grewal began his scientific career at the University of Cambridge, UK, where he held the prestigious Cambridge-Nehru scholarship. In 1993, he joined National Cancer Institute as a postdoctoral fellow to pursue his interests in the epigenetic control of gene expression. Apart from his pioneering work on the role of centromeric repeats in heterochromatin assembly, he showed that epigenetic imprints can be stably propagated through meiosis and in some instances inherited in cis. Dr. Grewal joined Cold Spring Harbor Laboratory as an Assistant Professor in 1998, and was promoted to Associate Professor position. In 2003, he joined National Cancer Institute, Bethesda as a Senior Investigator. He has been named an NIH Distinguished Investigator and is currently serving as the Chief of the Laboratory of Biochemistry and Molecular Biology and the Head of the Chromosome Biology Section of the Center for Cancer Research, National Cancer Institute. Dr. Grewal and colleagues discovered a highly conserved connection between RNAi and heterochromatin assembly. This important contribution was selected as Breakthrough of the Year 2002 by Science magazine. Three papers from Dr. Grewal's laboratory are cited for historic discoveries over the past 50 years by Nature. He is recipient of the prestigious Newcomb-Cleveland Prize, NIH Merit Award, and the NIH Directors’ award. Dr. Grewal has been elected to the US National Academy of Sciences and the American Academy of Arts and Sciences.
|Vanivilasini Balachandran||Laboratory Technician (Contr)|
|Jothy Dhakshnamoorthy M.S.||Laboratory Technician (Contr)|
|Hernan Diego Folco Ph.D.||Staff Scientist|
|Pamela Gallagher Ph.D.||Postdoctoral Fellow (CRTA)|
|Sahana Holla Ph.D.||Postdoctoral Fellow (Visiting)|
|Nathan Lee||Predoctoral Fellow|
|Lixia Pan Ph.D.||Postdoctoral Fellow (Visiting)|
|Tomoyasu Sugiyama Ph.D.||Research Fellow|
|Gobi Thillainadesan Ph.D.||Postdoctoral Fellow (Visiting)|
|Tommy Vo||Postdoctoral Fellow (CRTA)|
|Christopher Wellman||Lab Technician (Contr)|
|Martin Zofall Ph.D.||Staff Scientist|