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The impact of DNA methylation on CTCF-mediated 3D genome organization

Nature Structural & Molecular Biology volume 31, pages 404–412 (2024)Cite this article

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Abstract

Cytosine DNA methylation is a highly conserved epigenetic mark in eukaryotes. Although the role of DNA methylation at gene promoters and repetitive elements has been extensively studied, the function of DNA methylation in other genomic contexts remains less clear. In the nucleus of mammalian cells, the genome is spatially organized at different levels, and strongly influences myriad genomic processes. There are a number of factors that regulate the three-dimensional (3D) organization of the genome, with the CTCF insulator protein being among the most well-characterized. Pertinently, CTCF binding has been reported as being DNA methylation-sensitive in certain contexts, perhaps most notably in the process of genomic imprinting. Therefore, it stands to reason that DNA methylation may play a broader role in the regulation of chromatin architecture. Here we summarize the current understanding that is relevant to both the mammalian DNA methylation and chromatin architecture fields and attempt to assess the extent to which DNA methylation impacts the folding of the genome. The focus is in early embryonic development and cellular transitions when the epigenome is in flux, but we also describe insights from pathological contexts, such as cancer, in which the epigenome and 3D genome organization are misregulated.

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Fig. 1: Hierarchical layers of 3D genome organization.
Fig. 2: CTCF, its DNA-binding motif and the impact of 5meC.
Fig. 3: CTCF-mediated regulation of genomic imprints.
Fig. 4: Global DNA methylation and 3D genome dynamics in early mammalian development.
Fig. 5: Methyl-sensitive CTCF site misregulation in cancer.

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Acknowledgements

Work in the Greenberg group is supported by the European Research Council (ERC-StG-2019 DyNAmecs), a Laboratoire d’excellence Who Am I? (Labex 11-LABX-0071) Emerging Teams Grant and funds from the Agence National de Recherche (ANR, project ANR-21-CE12-0015-03). A.M.S. is supported by FRM (SPF202004011789) and ARC (ARCPDF12020070002563) postdoctoral fellowships. Work in the Noordermeer group is supported by funds from the ANR (projects ANR-21-CE12-0034-01, ANR-22-CE12-0016-03 and ANR-22-CE14-0021-02) and PlanCancer (19CS145-00).

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  1. Université Paris Cité, CNRS, Institut Jacques Monod, Paris, France

    Ana Monteagudo-Sánchez & Maxim V. C. Greenberg

  2. Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette, France

    Daan Noordermeer

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A.M.-S., D.N. and M.V.C.G. jointly conceived, wrote and edited this Review.

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Monteagudo-Sánchez, A., Noordermeer, D. & Greenberg, M.V.C. The impact of DNA methylation on CTCF-mediated 3D genome organization. Nat Struct Mol Biol 31, 404–412 (2024). https://doi.org/10.1038/s41594-024-01241-6

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