Format

Send to

Choose Destination
Cell Rep. 2017 Jan 31;18(5):1079-1089. doi: 10.1016/j.celrep.2017.01.008.

Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming.

Author information

1
Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK. Electronic address: ines.milagre@babraham.ac.uk.
2
Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
3
Bioinformatics Group, The Babraham Institute, Cambridge CB22 3AT, UK.
4
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
5
Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK; Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. Electronic address: wolf.reik@babraham.ac.uk.

Abstract

Global DNA demethylation is an integral part of reprogramming processes in vivo and in vitro, but whether it occurs in the derivation of induced pluripotent stem cells (iPSCs) is not known. Here, we show that iPSC reprogramming involves both global and targeted demethylation, which are separable mechanistically and by their biological outcomes. Cells at intermediate-late stages of reprogramming undergo transient genome-wide demethylation, which is more pronounced in female cells. Global demethylation requires activation-induced cytidine deaminase (AID)-mediated downregulation of UHRF1 protein, and abolishing demethylation leaves thousands of hypermethylated regions in the iPSC genome. Independently of AID and global demethylation, regulatory regions, particularly ESC enhancers and super-enhancers, are specifically targeted for hypomethylation in association with transcription of the pluripotency network. Our results show that global and targeted DNA demethylation are conserved and distinct reprogramming processes, presumably because of their respective roles in epigenetic memory erasure and in the establishment of cell identity.

KEYWORDS:

AID; DNA methylation; UHRF1; gender differences; iPSCs; reprogramming

PMID:
28147265
PMCID:
PMC5300890
DOI:
10.1016/j.celrep.2017.01.008
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center