Epigenetic dysregulation from chromosomal transit in micronuclei

Abstract

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.

Repair of DNA double-strand breaks leaves heritable impairment to genome function

“…This post-repair chromatin fatigue potentially affects numerous genes within the topologically defined chromatin neighbourhood that encountered, and recovered from, a single DNA breakage. This phenomenon is distinct from the recently described micronuclei-associated transcriptional repression of genes after re-integration into the nuclear genome ( 61 , 62 ). As reported in these studies, chromosome fragments being ejected from the nucleus in the form of micronuclei are brought into contact with cytoplasmic factors and seem to inherit persistent DNA damage accompanied by heterochromatinization and transcriptional repression ( 61 ).…”

Micronucleus Is Not a Potent Inducer of cGAS-STING Pathway

“…Cytoplasmic chromatin fragments have been linked to inflammation and antitumor mechanisms due to their cGAS-accumulating potency (Dou et al, 2017;Glück et al, 2017;Harding et al, 2017;Mackenzie et al, 2017;Yang et al, 2017). However, our results argue against this hypothesis and suggest that MN is inert to cGAS-dependent innate immune pathway, raising the possibility that MN is more prone to developing chromosome abnormalities, including chromothripsis (Zhang et al, 2015;Ly et al, 2016Ly et al, , 2019Kneissig et al, 2019;Umbreit et al, 2020) and epigenetic abnormalities (Agustinus et al, 2023;MacDonald et al, 2023), even in cells with an intact cGAS-STING pathway. Although our current study is limited to the specific reporter system, cytoplasmic mtDNA release needs to be carefully considered for studying cGAS-dependent inflammatory responses in different cellular contexts with MN formation.…”

CDK4 and CDK6 upregulation promotes DNA replication stress, genomic instability and resistance to EGFR targeted therapy in lung cancer

“…First, we analyzed tumor DNA through WES or targeted exome sequencing, potentially masking the detection of sub-clonal populations with low abundance and limiting the analysis to the coding DNA regions. Copy number fluctuation of trans- and cis-intronic regulatory elements might also contribute to the evolution of TKI resistance in CDK4/6 amp, EGFRmt NSCLC and will be a subject of future analyses 49 . We also limited our investigation to canonical roles of CDK4/6 as cell cycle regulators, whereas their functions in regulating gene expression, cell metabolism and immune editing 50 will be further evaluated in expanded clinical cohorts, including other cancer types.…”