Synergistic Mechanisms of DNA Demethylation during Transition to Ground-State Pluripotency

Title: Synergistic Mechanisms of DNA Demethylation during Transition to Ground-State Pluripotency
Authors: Hackett, JA
Dietmann, S
Murakami, K
Down, TA
Leitch, HG
Surani, MA
Item 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.
Issue Date: 17-Dec-2013
Date of Acceptance: 25-Nov-2013
URI: http://hdl.handle.net/10044/1/62061
DOI: https://dx.doi.org/10.1016/j.stemcr.2013.11.010
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.
Keywords: 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
Animals
Cell Culture Techniques
Cell Differentiation
DNA Methylation
DNA-Binding Proteins
Embryonic Stem Cells
Female
Gene Knockout Techniques
Genomic Imprinting
Male
Mice
Pluripotent Stem Cells
Proto-Oncogene Proteins
Pluripotent Stem Cells
Animals
Mice
DNA-Binding Proteins
Proto-Oncogene Proteins
Cell Culture Techniques
Cell Differentiation
DNA Methylation
Genomic Imprinting
Female
Male
Embryonic Stem Cells
Gene Knockout Techniques
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
Online Publication Date: 2013-12-17
Appears in Collections:Clinical Sciences
Imaging Sciences
Faculty of Medicine



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