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

doi:10.1016/j.celrep.2019.10.031

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

68 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1974-1985
Number of pages	19
Journal	Cell Reports
Volume	29
Issue number	7
Early online date	12 Nov 2019
DOIs	https://doi.org/10.1016/j.celrep.2019.10.031
Publication status	Published - 12 Nov 2019
Externally published	Yes

Keywords

3D genome
DNA methylation
fluorescence in situ hybridization
Hi-C pluripotency
polycomb
reprogramming
ground state

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10.1016/j.celrep.2019.10.031Licence: CC BY

PIIS2211124719313312Final published version, 4.44 MBLicence: CC BY

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title = "DNA Methylation Directs Polycomb-Dependent 3D Genome Re-organization in Naive Pluripotency",

abstract = "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.",

keywords = "3D genome, DNA methylation, fluorescence in situ hybridization, Hi-C pluripotency, polycomb, reprogramming, ground state",

author = "Katy McLaughlin and Flyamer, \{Ilya M.\} and Thomson, \{John P.\} and Mjoseng, \{Heidi K.\} and Ruchi Shukla and Iain Williamson and Grimes, \{Graeme R.\} and Illingworth, \{Robert S.\} and Adams, \{Ian R.\} and Sari Pennings and Meehan, \{Richard R.\} and Bickmore, \{Wendy A.\}",

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doi = "10.1016/j.celrep.2019.10.031",

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AU - McLaughlin, Katy

AU - Flyamer, Ilya M.

AU - Thomson, John P.

AU - Mjoseng, Heidi K.

AU - Shukla, Ruchi

AU - Williamson, Iain

AU - Grimes, Graeme R.

AU - Illingworth, Robert S.

AU - Adams, Ian R.

AU - Pennings, Sari

AU - Meehan, Richard R.

AU - Bickmore, Wendy A.

PY - 2019/11/12

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N2 - 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.

AB - 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.

KW - 3D genome

KW - DNA methylation

KW - fluorescence in situ hybridization

KW - Hi-C pluripotency

KW - polycomb

KW - reprogramming

KW - ground state

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DO - 10.1016/j.celrep.2019.10.031

M3 - Article

SN - 2211-1247

VL - 29

SP - 1974

EP - 1985

JO - Cell Reports

JF - Cell Reports

IS - 7

ER -

DNA Methylation Directs Polycomb-Dependent 3D Genome Re-organization in Naive Pluripotency

Abstract

Keywords

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