Shiv Grewal, Ph.D.
NIH Distinguished Investigator
Laboratory of Biochemistry and Molecular Biology
Building 37, Room 6066
Bethesda, MD 20892
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.
Sugiyama T, Thillainadesan G, Chalamcharla VR, Meng Z, Balachandran V, Dhakshnamoorthy J, Zhou M, Grewal SIS. Enhancer of Rudimentary Cooperates with Conserved RNA-Processing Factors to Promote Meiotic mRNA Decay and Facultative Heterochromatin Assembly. Mol Cell. 2016;61(5):747-759.
Folco HD, Campbell CS, May KM, Espinoza CA, Oegema K, Hardwick KG, Grewal SI, Desai A. The CENP-A N-tail confers epigenetic stability to centromeres via the CENP-T branch of the CCAN in fission yeast. Curr Biol. 2015;25(3):348-56.
Mizuguchi T, Fudenberg G, Mehta S, Belton JM, Taneja N, Folco HD, FitzGerald P, Dekker J, Mirny L, Barrowman J, Grewal SIS. Cohesin-dependent globules and heterochromatin shape 3D genome architecture in S. pombe. Nature. 2014;516(7531):432-435.
Yamanaka S, Mehta S, Reyes-Turcu FE, Zhuang F, Fuchs RT, Rong Y, Robb GB, Grewal SI. RNAi triggered by specialized machinery silences developmental genes and retrotransposons. Nature. 2013;493(7433):557-60.
Lee NN, Chalamcharla VR, Reyes-Turcu F, Mehta S, Zofall M, Balachandran V, Dhakshnamoorthy J, Taneja N, Yamanaka S, Zhou M, Grewal SI. Mtr4-like protein coordinates nuclear RNA processing for heterochromatin assembly and for telomere maintenance. Cell. 2013;155(5):1061-74.
Related Scientific Focus Areas
Genetics and Genomics
Molecular Biology and Biochemistry
This page was last updated on February 4th, 2019