Project 2: Epigenetics of aging in S. cerevisiae and human cells

Project leader

Shelley Berger, PhD.
University of Pennsylvania

Description

While a number of chromatin regulating factors have been implicated in aging in yeast and other organisms, the direct regulatory role of chromatin during aging has yet to be elucidated.  The project takes a two-pronged approach to discovery, utilizing both mammalian and S. cerevisiae yeast models.

S. cerevisiae provides a tractable genetic model for replicative aging, since individual yeast cells divide a certain number of times and then cease to replicate.  A number of observations suggest that alterations of chromatin, including changes in histone covalent post-translational modifications, occur as yeast age, and these transitions may be evolutionarily conserved in metazoans, including mammals.  For example, altered levels of sirtuin enzymes, evolutionarily conserved NAD+-dependent deacetylases that target histones among other substrates, changes the kinetics of aging.  Loss of Sir2 causes more rapid aging and over-expression of Sir2 causes delayed aging. However, whether chromatin changes are an important aspect of aging is not well understood.

A simultaneous goal of this project is to determine whether histone post-translational modifications change as human cells age, and if they directly regulate aging. To answer this question, the first aim is to characterize the specific histone post-translational modifications that are occurring during the aging process in primary human cells by chromatin immunoprepitation (ChIP) and ChIP-sequencing. A secondary aim is to determine if/how the modifications are affecting age-related changes in the cells by directly targeting the enzymes responsible for creating the modifications. A final aim is to characterize the histone state of the senescent genome, in an effort to better understand the changes occurring at the chromatin level during aging.

Key Personnel

  • Weiwei Dang
  • Greg Donahue
  • Jean Dorsey
  • Rocco Perry
  • Parisha Shah
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