Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming
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 mec...
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doaj-d6019b55743b450794b8067750d217d82020-11-25T02:20:58ZengElsevierCell Reports2211-12472017-01-011851079108910.1016/j.celrep.2017.01.008Gender Differences in Global but Not Targeted Demethylation in iPSC ReprogrammingInês Milagre0Thomas M. Stubbs1Michelle R. King2Julia Spindel3Fátima Santos4Felix Krueger5Martin Bachman6Anne Segonds-Pichon7Shankar Balasubramanian8Simon R. Andrews9Wendy Dean10Wolf Reik11Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UKEpigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UKEpigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UKEpigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UKEpigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UKBioinformatics Group, The Babraham Institute, Cambridge CB22 3AT, UKDepartment of Chemistry, University of Cambridge, Cambridge CB2 1EW, UKBioinformatics Group, The Babraham Institute, Cambridge CB22 3AT, UKDepartment of Chemistry, University of Cambridge, Cambridge CB2 1EW, UKBioinformatics Group, The Babraham Institute, Cambridge CB22 3AT, UKEpigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UKEpigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UKGlobal 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.http://www.sciencedirect.com/science/article/pii/S2211124717300268reprogrammingiPSCsDNA methylationgender differencesAIDUHRF1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Inês Milagre Thomas M. Stubbs Michelle R. King Julia Spindel Fátima Santos Felix Krueger Martin Bachman Anne Segonds-Pichon Shankar Balasubramanian Simon R. Andrews Wendy Dean Wolf Reik |
spellingShingle |
Inês Milagre Thomas M. Stubbs Michelle R. King Julia Spindel Fátima Santos Felix Krueger Martin Bachman Anne Segonds-Pichon Shankar Balasubramanian Simon R. Andrews Wendy Dean Wolf Reik Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming Cell Reports reprogramming iPSCs DNA methylation gender differences AID UHRF1 |
author_facet |
Inês Milagre Thomas M. Stubbs Michelle R. King Julia Spindel Fátima Santos Felix Krueger Martin Bachman Anne Segonds-Pichon Shankar Balasubramanian Simon R. Andrews Wendy Dean Wolf Reik |
author_sort |
Inês Milagre |
title |
Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming |
title_short |
Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming |
title_full |
Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming |
title_fullStr |
Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming |
title_full_unstemmed |
Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming |
title_sort |
gender differences in global but not targeted demethylation in ipsc reprogramming |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2017-01-01 |
description |
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. |
topic |
reprogramming iPSCs DNA methylation gender differences AID UHRF1 |
url |
http://www.sciencedirect.com/science/article/pii/S2211124717300268 |
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