Epigenetic dysregulation from chromosomal transit in micronuclei

被引：55

作者：

Agustinus, Albert S. S. ^{[1
,2
]}

Al-Rawi, Duaa ^{[1
,3
]}

Dameracharla, Bhargavi ^{[4
]}

Raviram, Ramya ^{[5
]}

Jones, Bailey S. C. L. ^{[6
]}

Stransky, Stephanie ^{[7
]}

Scipioni, Lorenzo ^{[8
]}

Luebeck, Jens ^{[4
]}

Di Bona, Melody ^{[1
]}

Norkunaite, Danguole ^{[1
]}

Myers, Robert M. M. ^{[5
,9
]}

Duran, Mercedes ^{[1
]}

Choi, Seongmin ^{[10
]}

Weigelt, Britta ^{[11
]}

Yomtoubian, Shira ^{[12
]}

McPherson, Andrew ^{[10
]}

Toufektchan, Eleonore ^{[13
]}

Keuper, Kristina ^{[14
]}

Mischel, Paul S. S. ^{[15
]}

Mittal, Vivek ^{[1
,12
]}

Shah, Sohrab P. P. ^{[10
]}

Maciejowski, John ^{[13
]}

Storchova, Zuzana ^{[14
]}

Gratton, Enrico ^{[8
]}

Ly, Peter ^{[16
]}

Landau, Dan ^{[5
,17
]}

Bakhoum, Mathieu F. F. ^{[6
,18
,19
]}

Koche, Richard P. P. ^{[20
]}

Sidoli, Simone ^{[7
]}

Bafna, Vineet ^{[4
]}

David, Yael ^{[2
,21
,22
]}

Bakhoum, Samuel F. F. ^{[1
,23
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[2] Weill Cornell Med, Pharmacol Grad Program, New York, NY 10021 USA

[3] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY USA

[4] Univ Calif San Diego, Dept Comp Sci, La Jolla, CA USA

[5] New York Genome Ctr, New York, NY USA

[6] Yale Univ, Dept Ophthalmol & Visual Sci, Sch Med, New Haven, CT USA

[7] Albert Einstein Coll Med, Dept Biochem, New York, NY USA

[8] Univ Calif Irvine, Sch Engn, Irvine, CA USA

[9] Triinst MD PhD Program, New York, NY USA

[10] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, Computat Oncol, New York, NY USA

[11] Mem Sloan Kettering Canc Ctr, Dept Pathol & Lab Med, New York, NY USA

[12] Weill Cornell Med, Dept Cell & Dev Biol, New York, NY USA

[13] Mem Sloan Kettering Canc Ctr, Mol Biol Program, New York, NY USA

[14] Univ Kaiserslautern, Dept Mol Genet, Kaiserslautern, Germany

[15] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA USA

[16] Univ Texas Southwestern Med Ctr, Dept Pathol, Dallas, TX USA

[17] Weill Cornell Med, Meyer Canc Ctr, New York, NY USA

[18] Yale Univ, Dept Pathol, Sch Med, New Haven, CT USA

[19] Yale Univ, Yale Canc Ctr, New Haven, CT USA

[20] Mem Sloan Kettering Canc Ctr, Ctr Epigenet Res, New York, NY USA

[21] Mem Sloan Kettering Canc Ctr, Chem Biol Program, New York, NY 10065 USA

[22] Triinst PhD Program Chem Biol, New York, NY 10021 USA

[23] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10065 USA

来源：

NATURE | 2023年 / 619卷 / 7968期

关键词：

INSTABILITY; CANCER; GENOME; PULVERIZATION; CELLS; CGAS;

D O I：

10.1038/s41586-023-06084-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 micronuclei(5,6) 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.

引用

页码：176 / +

页数：38

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