Weill Cornell Medical College
Our goal is to discover and understand the mechanistic basis of epigenetic regulation of genomic integrity and aging. The most fundamental level of epigenetic regulation is provided by the packaging of our DNA together with histone proteins to make chromatin, and the opposite process of removal of histones from the DNA. These chromatin assembly and disassembly processes physically block or permit, respectively, access of the cellular machinery to the genetic information carried by our DNA, thereby playing a critical role in controlling all genomic processes. We focus on understanding how chromatin is disassembled and reassembled, in order to discover new mechanisms whereby chromatin regulates aging, gene expression and genomic integrity. Our studies use a combination of molecular genetics in budding yeast, mammalian tissue culture, CRISPR/Cas9 gRNA genetic screens, and biochemical approaches. The proteins and processes that we study are so highly conserved through eukaryotic evolution, that what we learn in the highly genetically malleable yeast system is directly relevant to the situation in humans. In addition to learning how chromatin regulates fundamental processes in the cell, our studies are helping us to understand how defects in the chromatin structure lead to gene dysfunction and genomic instability, in turn causing human aging and disease states including cancer and leukemia.
Our interests in the role of chromatin in aging have led us more recently to a comprehensive characterization of the replicative aging process in budding yeast, as a model for stem cell aging. We do this using a variety of cutting-edge technologies including microfluidics imaging of trapped individual cells over their lifespan, in order to identify processes that go wrong during aging and reverse these changes by genetic / environmental manipulations to extend lifespan. Our ultimate goal is to identify compounds or regimens that can be leveraged to extend human lifespan and healthspan.