Author:
Agustinus Albert,Raviram Ramya,Dameracharla Bhargavi,Luebeck Jens,Stransky Stephanie,Scipioni Lorenzo,Myers Robert M.,Bona Melody Di,Duran Mercedes,Weigelt Britta,Yomtoubian Shira,Toufektchan Eléonore,Mischel Paul S.,Mittal Vivek,Shah Sohrab,Maciejowski John,Gratton Enrico,Ly Peter,Bakhoum Mathieu F.,Landau Dan,Bafna Vineet,Sidoli Simone,David Yael,Bakhoum Samuel F.
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.
Publisher
Cold Spring Harbor Laboratory
Reference48 articles.
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4. Watkins, T.B.K. , et al., Pervasive chromosomal instability and karyotype order in tumour evolution. Nature, 2020.
5. Chromosome pulverization in human cells with micronuclei;J Natl Cancer Inst,1968
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