DNA methylation influences human centromere positioning and function
Catalina Salinas‐Luypaert, Danilo Dubocanin, Rosa Jooyoung Lee, Lorena Andrade Ruiz, Riccardo Gamba, Marine Grison, Léonid 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
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.