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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300890/ https://www.ncbi.nlm.nih.gov/pubmed/28147265 http://dx.doi.org/10.1016/j.celrep.2017.01.008 |
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author | Milagre, Inês Stubbs, Thomas M. King, Michelle R. Spindel, Julia Santos, Fátima Krueger, Felix Bachman, Martin Segonds-Pichon, Anne Balasubramanian, Shankar Andrews, Simon R. Dean, Wendy Reik, Wolf |
author_facet | Milagre, Inês Stubbs, Thomas M. King, Michelle R. Spindel, Julia Santos, Fátima Krueger, Felix Bachman, Martin Segonds-Pichon, Anne Balasubramanian, Shankar Andrews, Simon R. Dean, Wendy Reik, Wolf |
author_sort | Milagre, Inês |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-5300890 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-53008902017-02-17 Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming Milagre, Inês Stubbs, Thomas M. King, Michelle R. Spindel, Julia Santos, Fátima Krueger, Felix Bachman, Martin Segonds-Pichon, Anne Balasubramanian, Shankar Andrews, Simon R. Dean, Wendy Reik, Wolf Cell Rep Report 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. Cell Press 2017-01-31 /pmc/articles/PMC5300890/ /pubmed/28147265 http://dx.doi.org/10.1016/j.celrep.2017.01.008 Text en © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Report Milagre, Inês Stubbs, Thomas M. King, Michelle R. Spindel, Julia Santos, Fátima Krueger, Felix Bachman, Martin Segonds-Pichon, Anne Balasubramanian, Shankar Andrews, Simon R. Dean, Wendy Reik, Wolf Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming |
title | 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_short | Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming |
title_sort | gender differences in global but not targeted demethylation in ipsc reprogramming |
topic | Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300890/ https://www.ncbi.nlm.nih.gov/pubmed/28147265 http://dx.doi.org/10.1016/j.celrep.2017.01.008 |
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