Synergistic Mechanisms of DNA Demethylation during Transition to Ground-State Pluripotency
Author(s)
Type
Journal Article
Abstract
Pluripotent stem cells (PSCs) occupy a spectrum of reversible molecular states ranging from a naive ground-state in 2i, to metastable embryonic stem cells (ESCs) in serum, to lineage-primed epiblast stem cells (EpiSCs). To investigate the role of DNA methylation (5mC) across distinct pluripotent states, we mapped genome-wide 5mC and 5-hydroxymethycytosine (5hmC) in multiple PSCs. Ground-state ESCs exhibit an altered distribution of 5mC and 5hmC at regulatory elements and dramatically lower absolute levels relative to ESCs in serum. By contrast, EpiSCs exhibit increased promoter 5mC coupled with reduced 5hmC, which contributes to their developmental restriction. Switch to 2i triggers rapid onset of both the ground-state gene expression program and global DNA demethylation. Mechanistically, repression of de novo methylases by PRDM14 drives DNA demethylation at slow kinetics, whereas TET1/TET2-mediated 5hmC conversion enhances both the rate and extent of hypomethylation. These processes thus act synergistically during transition to ground-state pluripotency to promote a robust hypomethylated state.
Date Issued
2013-12-17
Date Acceptance
2013-11-25
Citation
STEM CELL REPORTS, 2013, 1 (6), pp.518-531
ISSN
2213-6711
Publisher
CELL PRESS
Start Page
518
End Page
531
Journal / Book Title
STEM CELL REPORTS
Volume
1
Issue
6
Copyright Statement
© 2013 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which
permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000336647100006&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Cell & Tissue Engineering
Cell Biology
EMBRYONIC STEM-CELLS
PRIMORDIAL GERM-CELLS
NAIVE PLURIPOTENCY
SELF-RENEWAL
ES CELLS
GENOME
METHYLATION
5-HYDROXYMETHYLCYTOSINE
5-METHYLCYTOSINE
HYPOMETHYLATION
Publication Status
Published
Date Publish Online
2013-12-17