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abstract
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As a function of age, the capacity for adult stem cells to self-renew declines. Self-renewal, the ability of a stem cell to divide repeatedly, is crucial to perpetuate a pool of pluripotent cells that can differentiate to supplant cells that die during the lifespan of the organism. Yet this essential property of stem cells remains poorly understood at the molecular level. This proposal is centered on elucidating the mechanism by which several recently appreciated chemical modifications to DNA bases contribute to stem cell maintenance. The TET family of enzymes that installs these modifications in the genome is crucial for both maintaining stem cells in a pluripotent state and allowing them to proliferate. My lab has developed evidence that these modifications recruit distinct binding proteins, but how is this modification selectively achieved and what is the function of these binding events in stem cell maintenance? I will test the overarching hypothesis that TET-modified DNA and cognate binding partners that we have identified constitute the first step in a novel epigenetic signaling pathway that controls stemness. With my preliminary data and considerable experience in protein/nucleic acid biochemistry and cell biology, my lab is well suited to address these fundamental questions. The work proposed critically examines whether the loss of self-renewal in aging adult stem cells is due to perturbation of this epigenetic pathway, and has the potential to greatly improve our understanding of the molecular mechanisms of stem cell maintenance that could enable better control of therapeutics to supplant aging or dead tissue.
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