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Neocentromeres fail to maintain DNA methylation boundaries, driving CENP-A drift, instability, and chromosome missegregation

Year: 2026
Type: article
Abstract: Centromere identity is specified by CENP-A, a histone H3 variant that epigenetically defines centromere position. How CENP-A is maintained at one location in rapidly evolving centromeric DNA is unknown. Using single-cell-derived clones of human cell lines, we demonstrate heterogeneity in CENP-A position within cell populations at neocentromeres and a native centromere. CENP-A heterogeneity is accompanied by heterogeneous DNA methylation patterns, with DNA methylation shifting according to CENP-A position. We demonstrate centromere epigenetic plasticity over extended proliferation, with native centromeres maintaining stable DNA methylation boundaries, but neocentromeres exhibiting DNA methylation instability, boundary loss, and increased missegregation. Finally, we show that neocentromeres are more sensitive to DNA methylation inhibition than native centromeres, and that this inhibition is accompanied by expanded CENP-A-enriched domains and increased missegregation. This study supports a role for DNA methylation boundaries in maintaining centromere position, stability, and function and highlights the intrinsic instability of DNA methylation at neocentromeres.
Source: Cell Reports
DOI: 10.1016/j.celrep.2026.117770
Authors: Megan A. Mahlke, Angela Enriquez, Lior Lumerman, Poulomi Nath, Cy Chittenden, Savannah Hoyt, Jonas Koeppel, Yuan Xu, Rebecca Raphael, Kylie Zaffina, Paul W. Hook, Winston Timp, Karen H. Miga, Peter J. Campbell, Rachel J. O’Neill, Nicolas Altemose, Yael Nechemia-Arbely
Institutions: University of Pittsburgh, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Stanford Medicine, Stanford University, University of Connecticut, UConn Health, Wellcome Sanger Institute, University of California, Santa Cruz, Johns Hopkins University, UPMC Health System
Language: English
Open Access status: gold
Estimated APC paid: $5,620
Funders: Howard Hughes Medical Institute, Searle Scholars Program, Chan Zuckerberg Initiative, National Institutes of Health, Center for Research Computing, University of Pittsburgh, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, Hillman Cancer Center, Medical Center, University of Pittsburgh
Awards: High-Throughput Computing for Genomics and Bioinformatics Research, Nanopore based profiling of epigenetic state, The Role of Retroelements in Centromere Function, G8887262216, Mechanisms of epigenetic assembly, maintenance and propagation of human centromeres, Cancer Center Support Grant
OpenAlex ID: W7196971800
FWCI: 8.586
Cites: 85
Cited by: 10
Related to: 10