Smith Lab

Our research his broadly focused on the cellular mechanisms of aging, with an emphasis on chromatin organization, epigenetics, and their regulatory intersections with metabolism. We primarily utilize the budding (baker’s) yeast, Saccharomyces cerevisiae, as a unicellular model system that is highly amenable to genetic manipulation and genome-wide genetic screening. We are especially interested in the role of Sir2 and other NAD-dependent histone deacetylases (the sirtuins) in the formation of repressive chromatin within the ribosomal DNA (rDNA), a highly repetitive tandem array that plays a major role in replicative lifespan (RLS), defined as the number of divisions a mother cell undergoes prior to senescence. Recently, our work on Sir2 has unexpectedly expanded to the regulation of condensin loading and chromosome III structure in relationship to the classic mating-type switching process. We are exploring the functional regulation of chromosome III and the rDNA locus using sequencing-based genomics methods such as Hi-C and Micro-C XL.

We are also interested in Sir2-independent mechanisms of aging in the context of chronological lifespan (CLS), defined as the number of days that non-dividing cells remain viable. We are investigating mechanisms by which glucose restriction and other beneficial interventions such methionine restriction or serine supplementation extend CLS. One of the benefits of the yeast system is the availability of numerous genome-wide resources such as a gene knockout or overexpression collections for screening purposes, which our lab utilizes extensively. Long term goals are applying the paradigms we uncover using the yeast system to the investigation of conserved chromatin and aging mechanisms in multicellular models for aging.