Salinas-Luypaert Catalina, Dubocanin Danilo, Lee Rosa Jooyoung, Andrade Ruiz Lorena, Gamba Riccardo, Grison Marine, Velikovsky Leonid, Angrisani Annapaola, Scelfo Andrea, Xu Yuan, Dumont Marie, Barra Viviana, Wilhelm Therese, Velasco Guillaume, Losito Marialucrezia, Wardenaar René, Francastel Claire, Foijer Floris, Kops Geert J P L, Miga Karen H, Altemose Nicolas, Fachinetti Daniele
Institut Curie, PSL Research University, Sorbonne Université, CNRS, UMR144 and UMR3664, Paris, France.
Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA.
Nat Genet. 2025 Sep 4. doi: 10.1038/s41588-025-02324-w.
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.
维持着丝粒的表观遗传特性对于防止基因组不稳定至关重要。着丝粒由组蛋白H3变体CENP-A在表观遗传上定义。先前在人类着丝粒中的研究表明，CENP-A与位于大量高甲基化重复序列内的低甲基化DNA区域相关，但这些DNA甲基化（DNAme）模式的功能重要性仍知之甚少。为了解决这个问题，我们开发了工具来干扰着丝粒DNAme，揭示其因果影响CENP-A定位。我们表明，甲基化的快速丧失导致着丝粒蛋白结合增加和着丝粒结构改变，导致非整倍体和细胞活力降低。我们还证明，着丝粒DNA的逐渐去甲基化促使细胞适应过程。总之，我们发现DNAme因果影响CENP-A定位和着丝粒功能，为着丝粒DNAme的病理改变提供了机制性见解。
