Get started
Work

Regulation of DNA demethylation by the XPC DNA repair complex in somatic and pluripotent stem cells

Year: 2017
Type: preprint
Abstract: Faithful resetting of the epigenetic memory of a somatic cell to a pluripotent state during cellular reprogramming requires DNA methylation to silence somatic gene expression and dynamic DNA demethylation to activate pluripotency gene transcription. The removal of methylated cytosines requires the base excision repair enzyme TDG, but the mechanism by which TDG-dependent DNA demethylation occurs in a rapid and site-specific manner remains unclear. Here we show that the XPC DNA repair complex is a potent accelerator of global and locus-specific DNA demethylation in somatic and pluripotent stem cells. XPC cooperates with TDG genome-wide to stimulate the turnover of essential intermediates by overcoming slow TDG-abasic product dissociation during active DNA demethylation. We further establish that DNA demethylation induced by XPC expression in somatic cells overcomes an early epigenetic barrier in cellular reprogramming and facilitates the generation of more robust induced pluripotent stem cells, characterized by enhanced pluripotency-associated gene expression and self-renewal capacity. Taken together with our previous studies establishing the XPC complex as a transcriptional coactivator, our findings underscore two distinct but complementary mechanisms by which XPC influences gene regulation by coordinating efficient TDG-mediated DNA demethylation along with active transcription during somatic cell reprogramming.
DOI: 10.1101/gad.295741.116
Institutions: Howard Hughes Medical Institute, California Institute for Regenerative Medicine, University of California, Berkeley, Brigham and Women's Hospital, Harvard University, Harvard Stem Cell Institute
Language: English
Open Access status: hybrid
Funders: Howard Hughes Medical Institute, California Institute for Regenerative Medicine, California Institute of Regenerative Medicine, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Center for Research Resources
Awards: Genome Sequencer FLX, University of California Berkeley Chemistry-Biology Interface Training Program, Transcriptional regulation of pluripotency in human embryonic stem cells, Stem cell-specific transcriptional control by dyskerin ribonucleoprotein complex, Interdisciplinary Training in Stem Cell Biology, Engineering and Medicine, Illumina Sequencer to Facilitate Functional Genomics at Berkeley
OpenAlex ID: W2616516736
Cites: 93
Cited by: 27
Related to: 10