DNA Methylation Directs Polycomb-Dependent 3D Genome Re-organization in Naive Pluripotency
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
Affiliations
Katy McLaughlin
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK
Ilya M. Flyamer
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK
John P. Thomson
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK
Heidi K. Mjoseng
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK
Ruchi Shukla
MRC 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, UK
Iain Williamson
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK
Graeme R. Grimes
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK
Robert S. Illingworth
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK
Ian R. Adams
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK
Sari Pennings
Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
Richard R. Meehan
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK; Corresponding author
Wendy A. Bickmore
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK; Corresponding author
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
