DNA methylation influences human centromere positioning and function
Year: 2025
Type: article
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.
Source: Nature Genetics
Authors: 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
Institutions: Centre National de la Recherche Scientifique, Université Paris Sciences et Lettres, Sorbonne Université, Dynamique du noyau, Biologie cellulaire et Cancer, Institut Curie, Stanford Medicine, Stanford University, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht, Oncode Institute, University of California, Santa Cruz, University of Palermo, Université Paris Cité, Epigénétique et Destin Cellulaire, University Medical Center Groningen, University of Groningen, Laboratoire de Biologie du Développement, Institut de Biologie Paris-Seine, Chan Zuckerberg Biohub San Francisco
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Awards: Paris Sciences et Lettres, A rare disease to decode the functional link between DNA methylation and maintenance of centromere integrity, Emerging role of the centromere in human lymphocyte proliferation and aging, G6759105742, Physics of the 2 infinities and the origins, Genetics and Developmental Biology Training Program
OpenAlex ID: W4413992995