Impairment of DNA Methylation Maintenance Is the Main Cause of Global Demethylation in Naive Embryonic Stem Cells

Ferdinand von Meyenn, Mario Iurlaro, Ehsan Habibi, Ning Qing Liu, Ali Salehzadeh-Yazdi, Fátima Santos, Edoardo Petrini, Inês Milagre, Miao Yu, Zhenqing Xie, Leonie I. Kroeze, Tatyana B. Nesterova, Joop H. Jansen, Hehuang Xie, Chuan He, Wolf Reik*, Hendrik G. Stunnenberg

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

126 Citations (Scopus)

Abstract

Global demethylation is part of a conserved program of epigenetic reprogramming to naive pluripotency. The transition from primed hypermethylated embryonic stem cells (ESCs) to naive hypomethylated ones (serum-to-2i) is a valuable model system for epigenetic reprogramming. We present a mathematical model, which accurately predicts global DNA demethylation kinetics. Experimentally, we show that the main drivers of global demethylation are neither active mechanisms (Aicda, Tdg, and Tet1-3) nor the reduction of de novo methylation. UHRF1 protein, the essential targeting factor for DNMT1, is reduced upon transition to 2i, and so is recruitment of the maintenance methylation machinery to replication foci. Concurrently, there is global loss of H3K9me2, which is needed for chromatin binding of UHRF1. These mechanisms synergistically enforce global DNA hypomethylation in a replication-coupled fashion. Our observations establish the molecular mechanism for global demethylation in naive ESCs, which has key parallels with those operating in primordial germ cells and early embryos.

Original languageEnglish
Pages (from-to)848-861
Number of pages14
JournalMolecular Cell
Volume62
Issue number6
DOIs
Publication statusPublished - 16 Jun 2016
Externally publishedYes

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