New Scholar Award in Aging
Shiv L. S. Grewal, Ph.D.
Cold Spring Harbor Laboratory

Heterochromatin Assembly and Replicative Life-Span in Fission Yeast

Heterochromatin is a description of transcriptionally 'silent,' condensed chromosomal regions which largely consist of repetitive sequences, located primarily at centromeres and telomeres. Recent studies have suggested that heterochromatin plays many important functions, including proper segregation of chromosomes during cell division and gene dosage compensation in mammals. Furthermore, it has been suggested that a gradual loss of heterochromatin structures might be associated with cellular and organismal aging. Despite its crucial functions in gene regulation and chromosome architecture, the underlying mechanisms for heterochromatin assembly remain largely unknown.

To understand how heterochromatin structures are established and maintained through many rounds of cell division, we are studying the gene-repression mechanism known as "silencing" in fission yeast. Earlier studies showed that silencing at the mating-type region, centromeres and telomeres of fission yeast is mediated through the assembly of repressed heterochromatin structures. Interestingly, heterochromatin assembly is controlled by an epigenetic mechanism whereby heritable changes other than a mutation in the DNA itself are passed on to the daughter cells. We found that nucleoprotein complexes provide cues for their own reassembly during cell division and help promote inheritance of the silenced state. Certain evolutionarily conserved proteins known as chromodomain proteins, as well as proteins involved in modification of histones play a crucial role in maintenance of heterochromatin-mediated silencing in fission yeast. Remarkably, mutation in one of these factors called Clr6, which shares homology to histone deacetylases, also reduces the replicative life-span of the cells providing a genetic link between heterochromatin assembly and cellular senescence. Our current research focuses on the analysis of a clr6 mutant for previously described aging related phenomena, such as telomere length, rDNA stability, chromosome segregation defects and redistribution of other know heterochromatin proteins. We are also purifying the Clr6 protein complex to identify its interacting partners, as well as characterizing additional mutants defective in maintenance of heterochromatic domains. These studies will test the hypothesis that dynamic reorganization of heterochromatin structures affects cellular aging.

Contact Dr. Grewal.