Repository logo
 

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

Published version
Peer-reviewed

Loading...
Thumbnail Image

Type

Article

Change log

Authors

von Meyenn, Ferdinand 
Iurlaro, Mario 
Habibi, Ehsan 
Liu, Ning Qing 
Salehzadeh-Yazdi, Ali 

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.

Description

Keywords

31 Biological Sciences, 3105 Genetics

Journal Title

Mol Cell

Conference Name

Journal ISSN

1097-2765
1097-4164

Volume Title

62

Publisher

Elsevier BV