Discovery of New Epigenetic Pathways Involved in Stem Cell Maintenance

2013 new Scholar Award in aging

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.  By isolating proteins from the pig brains, my lab has discovered that these DNA modifications recruit very specific binding proteins.  We are now testing 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 maintains stem cell properties.  Crucial to this putative pathway are specific recognition events that appear capable of distinguishing certain modified bases to the exclusion of more abundant precursors—we are in the process of defining the molecular principles of these interactions as well.  With our preliminary data and considerable experience in protein/nucleic acid biochemistry and cell biology, my lab is well suited to address these fundamental questions.  This work will critically examine 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.

Alex Ruthenburg Ph.D.
Chicago, University of