In this study mouse embryonic fibroblasts (MEFs) and hematopoietic stem cells (HSCs) were used to identify genes involved in the process of cellular aging. MEFs are able to undergo a distinct number of population doublings, after which they enter a state of irreversible growth arrest termed replicative senescence. Previous studies of others and us have shown that aging is regulated by an intrinsic genetic program. In order to identify candidate genes involved in senescence we assessed gene expression profiles of proliferating and senescent MEFs. Interestingly, a significant number of genes that was higher expressed in proliferating vs. senescent MEFs, are involved in epigenetic regulation of gene transcription by modulating histone methylation and deacetylation. The top candidate gene was Enhancer of zeste homolog 2 (Ezh2), a Polycomb group protein (PcG), involved in histone methylation and deacetylation and known to function as a negative regulator of gene transcription. It has been reported that Ezh2 is essential during development, since Ezh2-deficient mice die early during embryonic development. Ezh2 expression was rapidly downregulated during senescence in primary MEFs, but was readily detectable in spontaneously transformed cells. Retroviral overexpression of Ezh2 in primary MEFs resulted in bypassing the senescence program. In addition, overexpression of Ezh2 in spontaneously transformed MEFs increased proliferation rates. We found that Ezh2 is highly expressed in purified Lin−Sca-1+c-kit+ (LSK) HSCs. In agreement with MEF studies, terminal differentiation of stem cells in vitro resulted in rapid downregulation of Ezh2 expression. Furthermore, overexpression of Ezh2 in purified HSCs results in increased proliferation rate in vitro. Moreover, HSCs transduced with Ezh2 were enriched for CFU-GM activity. Ongoing studies will address whether overexpression of Ezh2 in stem cells will affect their self-renewal potential in vivo. In an extensive genetic screen we identified genes that correlate with Ezh2 expression in stem cells, potential targets or partners of Ezh2, among others Top2a, MKi67, Pcna, and Eed. These data were deposited in an on-line resource (www.WebQTL.org), to uncover genetic networks that are involved in regulating the process of aging.