@article{ba76c80f1cc346cf9e9dc0337e8bfec2,
title = "Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming",
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, gender differences, iPSCs, reprogramming, UHRF1",
author = "In{\^e}s Milagre and Stubbs, {Thomas M.} and King, {Michelle R.} and Julia Spindel and F{\'a}tima Santos and Felix Krueger and Martin Bachman and Anne Segonds-Pichon and Shankar Balasubramanian and Andrews, {Simon R.} and Wendy Dean and Wolf Reik",
note = "Funding Information: We would like to thank Laura Biggins for help with data analysis and the Silva and Liu labs for sharing reprogramming protocols. We would like to thank Jos{\'e} Silva and Cristina Rada for critical reading of the manuscript and helpful discussions. We would like to thank the members of W.R.{\textquoteright}s and Rugg-Gunn's labs for helpful discussions and Dr. Veronique Juvin (
[email protected]; http://www.sciartwork.com) for the design and creation of the model figure/graphical abstract. This work was funded by the Wellcome Trust (095645/Z/11/Z), BBSRC (BB/K010867/1), EU NoE Epigenesys, and FEBS (Long-term fellowship to I.M.). S.B. is a founder and shareholder in Cambridge Epigenetix, Ltd., an advisor and shareholder in Illumina, Inc., and a senior investigator of the Wellcome Trust (grant no. 099232/z/12/z). W.R. is a consultant and shareholder in Cambridge Epigenetix, Ltd. Publisher Copyright: {\textcopyright} 2017 The Author(s)",
year = "2017",
month = jan,
day = "31",
doi = "10.1016/j.celrep.2017.01.008",
language = "English",
volume = "18",
pages = "1079--1089",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}