TY - JOUR
T1 - Epigenetic dysregulation from chromosomal transit in micronuclei
AU - Agustinus, Albert S.
AU - Al-Rawi, Duaa
AU - Dameracharla, Bhargavi
AU - Raviram, Ramya
AU - Jones, Bailey S.C.L.
AU - Stransky, Stephanie
AU - Scipioni, Lorenzo
AU - Luebeck, Jens
AU - Di Bona, Melody
AU - Norkunaite, Danguole
AU - Myers, Robert M.
AU - Duran, Mercedes
AU - Choi, Seongmin
AU - Weigelt, Britta
AU - Yomtoubian, Shira
AU - McPherson, Andrew
AU - Toufektchan, Eléonore
AU - Keuper, Kristina
AU - Mischel, Paul S.
AU - Mittal, Vivek
AU - Shah, Sohrab P.
AU - Maciejowski, John
AU - Storchova, Zuzana
AU - Gratton, Enrico
AU - Ly, Peter
AU - Landau, Dan
AU - Bakhoum, Mathieu F.
AU - Koche, Richard P.
AU - Sidoli, Simone
AU - Bafna, Vineet
AU - David, Yael
AU - Bakhoum, Samuel F.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/7/6
Y1 - 2023/7/6
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-023-06084-7
DO - 10.1038/s41586-023-06084-7
M3 - Article
C2 - 37286593
AN - SCOPUS:85161346167
SN - 0028-0836
VL - 619
SP - 176
EP - 183
JO - Nature
JF - Nature
IS - 7968
ER -
