DNA Methylation Directs Polycomb-Dependent 3D Genome Re-organization in Naive Pluripotency
Summary: The DNA hypomethylation that occurs when embryonic stem cells (ESCs) are directed to the ground state of naive pluripotency by culturing in two small molecule inhibitors (2i) results in redistribution of polycomb (H3K27me3) away from its target loci. Here, we demonstrate that 3D genome orga...
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doaj-494966c0bb4449d6817be1b988d20ad12020-11-24T21:41:24ZengElsevierCell Reports2211-12472019-11-0129719741985.e6DNA Methylation Directs Polycomb-Dependent 3D Genome Re-organization in Naive PluripotencyKaty McLaughlin0Ilya M. Flyamer1John P. Thomson2Heidi K. Mjoseng3Ruchi Shukla4Iain Williamson5Graeme R. Grimes6Robert S. Illingworth7Ian R. Adams8Sari Pennings9Richard R. Meehan10Wendy A. Bickmore11MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UKMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UKMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UKMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UKMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK; Northern Institute for Cancer Research, Framlington Place, Medical Faculty, Newcastle upon Tyne NE2 4HH, UKMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UKMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UKMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UKMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UKCentre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UKMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK; Corresponding authorMRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK; Corresponding authorSummary: The DNA hypomethylation that occurs when embryonic stem cells (ESCs) are directed to the ground state of naive pluripotency by culturing in two small molecule inhibitors (2i) results in redistribution of polycomb (H3K27me3) away from its target loci. Here, we demonstrate that 3D genome organization is also altered in 2i, with chromatin decompaction at polycomb target loci and a loss of long-range polycomb interactions. By preventing DNA hypomethylation during the transition to the ground state, we are able to restore to ESC in 2i the H3K27me3 distribution, as well as polycomb-mediated 3D genome organization that is characteristic of primed ESCs grown in serum. However, these cells retain the functional characteristics of 2i ground-state ESCs. Our findings demonstrate the central role of DNA methylation in shaping major aspects of 3D genome organization but caution against assuming causal roles for the epigenome and 3D genome in gene regulation and function in ESCs. : McLaughlin et al. demonstrate that the global DNA methylation state directs the PRC-dependent 3D organization of mouse ESCs and probably early blastocysts. Their findings highlight a central role for DNA methylation and its influence on polycomb, in shaping major aspects of 3D genome organization in stem cells. Keywords: 3D genome, DNA methylation, fluorescence in situ hybridization, Hi-C, pluripotency, polycomb, reprogramming, ground statehttp://www.sciencedirect.com/science/article/pii/S2211124719313312 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Katy McLaughlin Ilya M. Flyamer John P. Thomson Heidi K. Mjoseng Ruchi Shukla Iain Williamson Graeme R. Grimes Robert S. Illingworth Ian R. Adams Sari Pennings Richard R. Meehan Wendy A. Bickmore |
spellingShingle |
Katy McLaughlin Ilya M. Flyamer John P. Thomson Heidi K. Mjoseng Ruchi Shukla Iain Williamson Graeme R. Grimes Robert S. Illingworth Ian R. Adams Sari Pennings Richard R. Meehan Wendy A. Bickmore DNA Methylation Directs Polycomb-Dependent 3D Genome Re-organization in Naive Pluripotency Cell Reports |
author_facet |
Katy McLaughlin Ilya M. Flyamer John P. Thomson Heidi K. Mjoseng Ruchi Shukla Iain Williamson Graeme R. Grimes Robert S. Illingworth Ian R. Adams Sari Pennings Richard R. Meehan Wendy A. Bickmore |
author_sort |
Katy McLaughlin |
title |
DNA Methylation Directs Polycomb-Dependent 3D Genome Re-organization in Naive Pluripotency |
title_short |
DNA Methylation Directs Polycomb-Dependent 3D Genome Re-organization in Naive Pluripotency |
title_full |
DNA Methylation Directs Polycomb-Dependent 3D Genome Re-organization in Naive Pluripotency |
title_fullStr |
DNA Methylation Directs Polycomb-Dependent 3D Genome Re-organization in Naive Pluripotency |
title_full_unstemmed |
DNA Methylation Directs Polycomb-Dependent 3D Genome Re-organization in Naive Pluripotency |
title_sort |
dna methylation directs polycomb-dependent 3d genome re-organization in naive pluripotency |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2019-11-01 |
description |
Summary: The DNA hypomethylation that occurs when embryonic stem cells (ESCs) are directed to the ground state of naive pluripotency by culturing in two small molecule inhibitors (2i) results in redistribution of polycomb (H3K27me3) away from its target loci. Here, we demonstrate that 3D genome organization is also altered in 2i, with chromatin decompaction at polycomb target loci and a loss of long-range polycomb interactions. By preventing DNA hypomethylation during the transition to the ground state, we are able to restore to ESC in 2i the H3K27me3 distribution, as well as polycomb-mediated 3D genome organization that is characteristic of primed ESCs grown in serum. However, these cells retain the functional characteristics of 2i ground-state ESCs. Our findings demonstrate the central role of DNA methylation in shaping major aspects of 3D genome organization but caution against assuming causal roles for the epigenome and 3D genome in gene regulation and function in ESCs. : McLaughlin et al. demonstrate that the global DNA methylation state directs the PRC-dependent 3D organization of mouse ESCs and probably early blastocysts. Their findings highlight a central role for DNA methylation and its influence on polycomb, in shaping major aspects of 3D genome organization in stem cells. Keywords: 3D genome, DNA methylation, fluorescence in situ hybridization, Hi-C, pluripotency, polycomb, reprogramming, ground state |
url |
http://www.sciencedirect.com/science/article/pii/S2211124719313312 |
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