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Peer-reviewedCC BY-NCCell Reports

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

  • Megan A. Mahlke1
  • Angela Enriquez1
  • Lior Lumerman1
  • Poulomi Nath1
  • Cy Chittenden2
  • Savannah J. Hoyt3
  • Jonas Koeppel4
  • Yuan Xu5
  • Rebecca Raphael1
  • Kylie Zaffina1
  • Paul W. Hook6
  • Winston Timp6
5 more authors
  • Karen H. Miga5
  • Peter J. Campbell4
  • Rachel J. O’Neill7,8
  • Nicolas Altemose2
  • Yael Nechemia‐Arbely9
9 affiliations
  1. 1UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
  2. 2Department of Genetics, School of Medicine, Stanford University, Stanford, CA, USA
  3. 3Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, USA; Department of Genetics and Genome Sciences, UConn Health, Farmington CT, USA
  4. 4Somatic Genomics Programme, Wellcome Sanger Institute, Hinxton, UK
  5. 5UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA
  6. 6Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
  7. 7Department of Genetics and Genome Sciences, UConn Health, Farmington CT, USA
  8. 8Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, USA
  9. 9UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address: [email protected]
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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.

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Cite

BibTeXRIS
BibTeX
@article{mahlke2026neocentromeres,
  title = {{Neocentromeres fail to maintain DNA methylation boundaries, driving CENP-A drift, instability, and chromosome missegregation}},
  author = {Megan A. Mahlke and Angela Enriquez and Lior Lumerman and Poulomi Nath and Cy Chittenden and Savannah J. Hoyt and Jonas Koeppel and Yuan Xu and Rebecca Raphael and Kylie Zaffina and Paul W. Hook and Winston Timp and Karen H. Miga and Peter J. Campbell and Rachel J. O’Neill and Nicolas Altemose and Yael Nechemia‐Arbely},
  journal = {Cell Reports},
  year = {2026},
  month = aug,
  doi = {10.1016/j.celrep.2026.117770},
  url = {https://doi.org/10.1016/j.celrep.2026.117770},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Neocentromeres fail to maintain DNA methylation boundaries, driving CENP-A drift, instability, and chromosome missegregation
AU  - Megan A. Mahlke
AU  - Angela Enriquez
AU  - Lior Lumerman
AU  - Poulomi Nath
AU  - Cy Chittenden
AU  - Savannah J. Hoyt
AU  - Jonas Koeppel
AU  - Yuan Xu
AU  - Rebecca Raphael
AU  - Kylie Zaffina
AU  - Paul W. Hook
AU  - Winston Timp
AU  - Karen H. Miga
AU  - Peter J. Campbell
AU  - Rachel J. O’Neill
AU  - Nicolas Altemose
AU  - Yael Nechemia‐Arbely
PY  - 2026
DA  - 2026/08/01
JO  - Cell Reports
DO  - 10.1016/j.celrep.2026.117770
UR  - https://doi.org/10.1016/j.celrep.2026.117770
AB  - 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.
SN  - 2211-1247
SN  - 2639-1856
ER  -