DNA methylation influences human centromere positioning and function

Catalina Salinas-Luypaert; Danilo Dubocanin; Rosa Jooyoung Lee; Lorena Andrade Ruiz; Riccardo Gamba; Marine Grison; Leonid Velikovsky; Annapaola Angrisani; Andrea Scelfo; Yuan Xu; Marie Dumont; Viviana Barra; Therese Wilhelm; Guillaume Velasco; Marialucrezia Losito; René Wardenaar; Claire Francastel; Floris Foijer; Geert J P L Kops; Karen H Miga; Nicolas Altemose; Daniele Fachinetti

doi:10.1038/s41588-025-02324-w

DNA methylation influences human centromere positioning and function

Catalina Salinas-Luypaert
, Danilo Dubocanin
, Rosa Jooyoung Lee
, Lorena Andrade Ruiz
, Riccardo Gamba
, Marine Grison
, Leonid Velikovsky
, Annapaola Angrisani
, Andrea Scelfo
, Yuan Xu
, Marie Dumont
, Viviana Barra
, Therese Wilhelm
, Guillaume Velasco
, Marialucrezia Losito
, René Wardenaar
, Claire Francastel
, Floris Foijer
, Geert J P L Kops
, Karen H Miga

Nicolas Altemose^*, Daniele Fachinetti^*

^*Corresponding author for this work

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

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Abstract

Maintaining the epigenetic identity of centromeres is essential to prevent genome instability. Centromeres are epigenetically defined by the histone H3 variant CENP-A. Prior work in human centromeres has shown that CENP-A is associated with regions of hypomethylated DNA located within large arrays of hypermethylated repeats, but the functional importance of these DNA methylation (DNAme) patterns remains poorly understood. To address this, we developed tools to perturb centromeric DNAme, revealing that it causally influences CENP-A positioning. We show that rapid loss of methylation results in increased binding of centromeric proteins and alterations in centromere architecture, leading to aneuploidy and reduced cell viability. We also demonstrate that gradual centromeric DNA demethylation prompts a process of cellular adaptation. Altogether, we find that DNAme causally influences CENP-A localization and centromere function, offering mechanistic insights into pathological alterations of centromeric DNAme.

Original language	English
Pages (from-to)	2509-2521
Number of pages	13
Journal	Nature genetics
Volume	57
Issue number	10
Early online date	4 Sept 2025
DOIs	https://doi.org/10.1038/s41588-025-02324-w
Publication status	Published - Oct 2025

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10.1038/s41588-025-02324-wLicence: CC BY-NC-ND

DNA methylation influences human centromere positioning and functionFinal published version, 20.4 MBLicence: CC BY-NC-ND

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Salinas-Luypaert, C., Dubocanin, D., Lee, R. J., Andrade Ruiz, L., Gamba, R., Grison, M., Velikovsky, L., Angrisani, A., Scelfo, A., Xu, Y., Dumont, M., Barra, V., Wilhelm, T., Velasco, G., Losito, M., Wardenaar, R., Francastel, C., Foijer, F., Kops, G. J. P. L., ... Fachinetti, D. (2025). DNA methylation influences human centromere positioning and function. Nature genetics, 57(10), 2509-2521. https://doi.org/10.1038/s41588-025-02324-w

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title = "DNA methylation influences human centromere positioning and function",

abstract = "Maintaining the epigenetic identity of centromeres is essential to prevent genome instability. Centromeres are epigenetically defined by the histone H3 variant CENP-A. Prior work in human centromeres has shown that CENP-A is associated with regions of hypomethylated DNA located within large arrays of hypermethylated repeats, but the functional importance of these DNA methylation (DNAme) patterns remains poorly understood. To address this, we developed tools to perturb centromeric DNAme, revealing that it causally influences CENP-A positioning. We show that rapid loss of methylation results in increased binding of centromeric proteins and alterations in centromere architecture, leading to aneuploidy and reduced cell viability. We also demonstrate that gradual centromeric DNA demethylation prompts a process of cellular adaptation. Altogether, we find that DNAme causally influences CENP-A localization and centromere function, offering mechanistic insights into pathological alterations of centromeric DNAme.",

author = "Catalina Salinas-Luypaert and Danilo Dubocanin and Lee, \{Rosa Jooyoung\} and \{Andrade Ruiz\}, Lorena and Riccardo Gamba and Marine Grison and Leonid Velikovsky and Annapaola Angrisani and Andrea Scelfo and Yuan Xu and Marie Dumont and Viviana Barra and Therese Wilhelm and Guillaume Velasco and Marialucrezia Losito and Ren{\'e} Wardenaar and Claire Francastel and Floris Foijer and Kops, \{Geert J P L\} and Miga, \{Karen H\} and Nicolas Altemose and Daniele Fachinetti",

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doi = "10.1038/s41588-025-02324-w",

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Salinas-Luypaert, C, Dubocanin, D, Lee, RJ, Andrade Ruiz, L, Gamba, R, Grison, M, Velikovsky, L, Angrisani, A, Scelfo, A, Xu, Y, Dumont, M, Barra, V, Wilhelm, T, Velasco, G, Losito, M, Wardenaar, R, Francastel, C, Foijer, F, Kops, GJPL, Miga, KH, Altemose, N & Fachinetti, D 2025, 'DNA methylation influences human centromere positioning and function', Nature genetics, vol. 57, no. 10, pp. 2509-2521. https://doi.org/10.1038/s41588-025-02324-w

TY - JOUR

T1 - DNA methylation influences human centromere positioning and function

AU - Salinas-Luypaert, Catalina

AU - Dubocanin, Danilo

AU - Lee, Rosa Jooyoung

AU - Andrade Ruiz, Lorena

AU - Gamba, Riccardo

AU - Grison, Marine

AU - Velikovsky, Leonid

AU - Angrisani, Annapaola

AU - Scelfo, Andrea

AU - Xu, Yuan

AU - Dumont, Marie

AU - Barra, Viviana

AU - Wilhelm, Therese

AU - Velasco, Guillaume

AU - Losito, Marialucrezia

AU - Wardenaar, René

AU - Francastel, Claire

AU - Foijer, Floris

AU - Kops, Geert J P L

AU - Miga, Karen H

AU - Altemose, Nicolas

AU - Fachinetti, Daniele

PY - 2025/10

Y1 - 2025/10

N2 - Maintaining the epigenetic identity of centromeres is essential to prevent genome instability. Centromeres are epigenetically defined by the histone H3 variant CENP-A. Prior work in human centromeres has shown that CENP-A is associated with regions of hypomethylated DNA located within large arrays of hypermethylated repeats, but the functional importance of these DNA methylation (DNAme) patterns remains poorly understood. To address this, we developed tools to perturb centromeric DNAme, revealing that it causally influences CENP-A positioning. We show that rapid loss of methylation results in increased binding of centromeric proteins and alterations in centromere architecture, leading to aneuploidy and reduced cell viability. We also demonstrate that gradual centromeric DNA demethylation prompts a process of cellular adaptation. Altogether, we find that DNAme causally influences CENP-A localization and centromere function, offering mechanistic insights into pathological alterations of centromeric DNAme.

AB - Maintaining the epigenetic identity of centromeres is essential to prevent genome instability. Centromeres are epigenetically defined by the histone H3 variant CENP-A. Prior work in human centromeres has shown that CENP-A is associated with regions of hypomethylated DNA located within large arrays of hypermethylated repeats, but the functional importance of these DNA methylation (DNAme) patterns remains poorly understood. To address this, we developed tools to perturb centromeric DNAme, revealing that it causally influences CENP-A positioning. We show that rapid loss of methylation results in increased binding of centromeric proteins and alterations in centromere architecture, leading to aneuploidy and reduced cell viability. We also demonstrate that gradual centromeric DNA demethylation prompts a process of cellular adaptation. Altogether, we find that DNAme causally influences CENP-A localization and centromere function, offering mechanistic insights into pathological alterations of centromeric DNAme.

UR - https://www.scopus.com/pages/publications/105015211984

U2 - 10.1038/s41588-025-02324-w

DO - 10.1038/s41588-025-02324-w

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C2 - 40908343

SN - 1061-4036

VL - 57

SP - 2509

EP - 2521

JO - Nature genetics

JF - Nature genetics

IS - 10

ER -

DNA methylation influences human centromere positioning and function

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