DNA methylation influences human centromere positioning and function
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.
Authors
- Daniele Fachinetti (ORCID: https://orcid.org/0000-0002-8795-6771)
- Therese Wilhelm (ORCID: https://orcid.org/0000-0003-3178-9174)
- Catalina Salinas‐Luypaert (ORCID: https://orcid.org/0000-0003-1194-4536)
- Karen H. Miga (ORCID: https://orcid.org/0000-0002-3670-4507)
- Rosa Jooyoung Lee (ORCID: https://orcid.org/0009-0009-0553-4451)
- Léonid Velikovsky (ORCID: https://orcid.org/0000-0003-2679-4155)
- Marie Dumont (ORCID: https://orcid.org/0000-0002-0636-0731)
- Annapaola Angrisani (ORCID: https://orcid.org/0000-0002-3407-7669)
- Danilo Dubocanin (ORCID: https://orcid.org/0000-0003-0330-5814)
- Lorena Andrade Ruiz
- Nicolas Altemose (ORCID: https://orcid.org/0000-0002-7231-6026)
- Guillaume Velasco (ORCID: https://orcid.org/0000-0002-3620-8810)
- Viviana Barra (ORCID: https://orcid.org/0000-0002-7186-4485)
- Andrea Scelfo (ORCID: https://orcid.org/0000-0001-8767-0688)
- Riccardo Gamba (ORCID: https://orcid.org/0000-0002-6306-4955)
- Marialucrezia Losito (ORCID: https://orcid.org/0000-0001-8097-5139)
- Claire Francastel (ORCID: https://orcid.org/0000-0002-6353-4320)
- Geert J.P.L. Kops (ORCID: https://orcid.org/0000-0003-3555-5295)
- René Wardenaar (ORCID: https://orcid.org/0000-0001-9891-1897)
- Floris Foijer (ORCID: https://orcid.org/0000-0003-0989-3127)
- Marine Grison
- Yuan Xu (ORCID: https://orcid.org/0000-0002-7814-7542)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Royal Netherlands Academy of Arts and Sciences (NL)
- University Medical Center Groningen (NL)
- University of Groningen (NL)
- University of California, Santa Cruz (US)
- Université Paris Cité (FR)
- Université Paris Sciences et Lettres (FR)
- University Medical Center Utrecht (NL)
- Sorbonne Université (FR)
- Institut de Biologie Paris-Seine (FR)
- Oncode Institute (NL)
- Chan Zuckerberg Initiative (United States) (US)
- Epigénétique et Destin Cellulaire (FR)
- Dynamique du noyau (FR)
- Biologie cellulaire et Cancer (FR)
- University of Palermo (IT)
- Stanford University (US)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-09-04
- DOI
- https://doi.org/10.1038/s41588-025-02324-w
- Citations
- 10
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 8.06
Funders
- Searle Scholars Program
- Agence Nationale de la Recherche