Epigenetic dysregulation from chromosomal transit in micronuclei

Albert S. Agustinus, Duaa Al-Rawi, Bhargavi Dameracharla, Ramya Raviram, Bailey S. C. L. Jones, Stephanie Stransky, Lorenzo Scipioni, Jens Luebeck, Melody Bona, Danguole Norkunaite, Robert M. Myers, Mercedes Duran, Seongmin Choi, Britta Weigelt, Shira Yomtoubian, Andrew McPherson, Eléonore Toufektchan, Kristina Keuper, Paul S. Mischel, Vivek Mittal, Sohrab P. Shah, John Maciejowski, Zuzana Storchova, Enrico Gratton, Peter Ly, Dan Landau, Mathieu F. Bakhoum, Richard P. Koche, Simone Sidoli, Vineet Bafna, Yael David () and Samuel F. Bakhoum ()
Additional contact information
Albert S. Agustinus: Memorial Sloan Kettering Cancer Center
Duaa Al-Rawi: Memorial Sloan Kettering Cancer Center
Bhargavi Dameracharla: University of California, San Diego
Ramya Raviram: New York Genome Center
Bailey S. C. L. Jones: Yale University School of Medicine
Stephanie Stransky: Albert Einstein College of Medicine
Lorenzo Scipioni: University of California, Irvine
Jens Luebeck: University of California, San Diego
Melody Bona: Memorial Sloan Kettering Cancer Center
Danguole Norkunaite: Memorial Sloan Kettering Cancer Center
Robert M. Myers: New York Genome Center
Mercedes Duran: Memorial Sloan Kettering Cancer Center
Seongmin Choi: Memorial Sloan Kettering Cancer Center
Britta Weigelt: Memorial Sloan Kettering Cancer Center
Shira Yomtoubian: Weill Cornell Medicine
Andrew McPherson: Memorial Sloan Kettering Cancer Center
Eléonore Toufektchan: Memorial Sloan Kettering Cancer Center
Kristina Keuper: University of Kaiserslautern
Paul S. Mischel: Stanford University
Vivek Mittal: Memorial Sloan Kettering Cancer Center
Sohrab P. Shah: Memorial Sloan Kettering Cancer Center
John Maciejowski: Memorial Sloan Kettering Cancer Center
Zuzana Storchova: University of Kaiserslautern
Enrico Gratton: University of California, Irvine
Peter Ly: University of Texas Southwestern Medical Center
Dan Landau: New York Genome Center
Mathieu F. Bakhoum: Yale University School of Medicine
Richard P. Koche: Memorial Sloan Kettering Cancer Center
Simone Sidoli: Albert Einstein College of Medicine
Vineet Bafna: University of California, San Diego
Yael David: Weill Cornell Medicine
Samuel F. Bakhoum: Memorial Sloan Kettering Cancer Center

Nature, 2023, vol. 619, issue 7968, 176-183

Abstract: Abstract Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers1–4, but whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei5,6 and subsequent rupture of the micronuclear envelope7 profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice, as well as in cancer and non-transformed cells. Some of the changes in histone PTMs occur because of the rupture of the micronuclear envelope, whereas others are inherited from mitotic abnormalities before the micronucleus is formed. Using orthogonal approaches, we demonstrate that micronuclei exhibit extensive differences in chromatin accessibility, with a strong positional bias between promoters and distal or intergenic regions, in line with observed redistributions of histone PTMs. Inducing CIN causes widespread epigenetic dysregulation, and chromosomes that transit in micronuclei experience heritable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, as well as altering genomic copy number, CIN promotes epigenetic reprogramming and heterogeneity in cancer.

Date: 2023
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DOI: 10.1038/s41586-023-06084-7

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