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.
