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Epigenetic dysregulation from chromosomal transit in micronuclei

Albert Agustinus, Ramya Raviram, Bhargavi Dameracharla, Jens Luebeck, Stephanie Stransky, Lorenzo Scipioni, Robert M. Myers, Melody Di Bona, Mercedes Duran, Britta Weigelt, Shira Yomtoubian, Eléonore Toufektchan, Paul S. Mischel, Vivek Mittal, Sohrab Shah, John Maciejowski, Enrico Gratton, Peter Ly, Mathieu F. Bakhoum, Dan Landau, Vineet Bafna, Simone Sidoli, Yael David, Samuel F. Bakhoum
doi: https://doi.org/10.1101/2022.01.12.475944
Albert Agustinus
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
2Pharmacology Graduate Program, Weill Cornell Medicine, New York, NY
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Ramya Raviram
3New York Genome Center, New York, NY
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Bhargavi Dameracharla
4Department of Computer Science, University of California San Diego, La Jolla, CA
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Jens Luebeck
4Department of Computer Science, University of California San Diego, La Jolla, CA
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Stephanie Stransky
5Department of Biochemistry, Albert Einstein College of Medicine, New York, NY
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Lorenzo Scipioni
6School of Engineering, University of California Irvine, Irvine, CA
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Robert M. Myers
3New York Genome Center, New York, NY
7Tri-institutional MD-PhD Program, New York, NY
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Melody Di Bona
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
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Mercedes Duran
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
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Britta Weigelt
8Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
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Shira Yomtoubian
9Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY
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Eléonore Toufektchan
10Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY
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Paul S. Mischel
11Department of Pathology, Stanford University, School of Medicine and Stanford ChEM-H, Stanford, CA
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Vivek Mittal
9Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY
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Sohrab Shah
12Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY
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John Maciejowski
10Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY
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Enrico Gratton
6School of Engineering, University of California Irvine, Irvine, CA
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Peter Ly
13Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX
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Mathieu F. Bakhoum
14Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, CT
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Dan Landau
3New York Genome Center, New York, NY
15Meyer Cancer Center, Weill Cornell Medicine, New York, NY
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Vineet Bafna
4Department of Computer Science, University of California San Diego, La Jolla, CA
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Simone Sidoli
5Department of Biochemistry, Albert Einstein College of Medicine, New York, NY
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Yael David
2Pharmacology Graduate Program, Weill Cornell Medicine, New York, NY
16Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY
17Tri-institutional Program in Chemical Biology, New York, NY
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  • For correspondence: samuel.bakhoum@gmail.com davidshy@mskcc.org
Samuel F. Bakhoum
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
18Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
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  • For correspondence: samuel.bakhoum@gmail.com davidshy@mskcc.org
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Abstract

Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers [1-4], yet whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei [5, 6], and subsequent micronuclear envelope rupture [7] profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice as well as cancer and non-transformed cells. Some of the changes to histone PTMs occur due to micronuclear envelope rupture whereas others are inherited from mitotic abnormalities prior to micronucleus formation. Using orthogonal techniques, we show that micronuclei exhibit extensive differences in chromatin accessibility with a strong positional bias between promoters and distal or intergenic regions. Finally, we show that inducing CIN engenders widespread epigenetic dysregulation and that chromosomes which transit in micronuclei experience durable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, in addition to genomic copy number alterations, CIN can serve as a vehicle for epigenetic reprogramming and heterogeneity in cancer.

Competing Interest Statement

SFB owns equity in, receives compensation from, and serves as a consultant and the Scientific Advisory Board and Board of Directors of Volastra Therapeutics Inc. VB is a co-founder, consultant, SAB member and has equity interest in Boundless Bio, inc. and Abterra, Inc. The terms of this arrangement have been reviewed and ap-proved by the University of California, San Diego in ac-cordance with its conflict-of-interest policies. PSM is a co-founder of Boundless Bio, Inc. He has equity in the company and chairs the Scientific Advisory Board, for which he is compensated. BW reports ad hoc member-ship of the scientific advisory board of Repare Thera-peutics, outside the submitted work. The remaining au-thors declare no conflicts of interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted January 12, 2022.
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Epigenetic dysregulation from chromosomal transit in micronuclei
Albert Agustinus, Ramya Raviram, Bhargavi Dameracharla, Jens Luebeck, Stephanie Stransky, Lorenzo Scipioni, Robert M. Myers, Melody Di Bona, Mercedes Duran, Britta Weigelt, Shira Yomtoubian, Eléonore Toufektchan, Paul S. Mischel, Vivek Mittal, Sohrab Shah, John Maciejowski, Enrico Gratton, Peter Ly, Mathieu F. Bakhoum, Dan Landau, Vineet Bafna, Simone Sidoli, Yael David, Samuel F. Bakhoum
bioRxiv 2022.01.12.475944; doi: https://doi.org/10.1101/2022.01.12.475944
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Epigenetic dysregulation from chromosomal transit in micronuclei
Albert Agustinus, Ramya Raviram, Bhargavi Dameracharla, Jens Luebeck, Stephanie Stransky, Lorenzo Scipioni, Robert M. Myers, Melody Di Bona, Mercedes Duran, Britta Weigelt, Shira Yomtoubian, Eléonore Toufektchan, Paul S. Mischel, Vivek Mittal, Sohrab Shah, John Maciejowski, Enrico Gratton, Peter Ly, Mathieu F. Bakhoum, Dan Landau, Vineet Bafna, Simone Sidoli, Yael David, Samuel F. Bakhoum
bioRxiv 2022.01.12.475944; doi: https://doi.org/10.1101/2022.01.12.475944

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