Epigenetic dysregulation from chromosomal transit in micronuclei

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.

The fate of extra centrosomes in newly formed tetraploid cells: should I stay, or should I go?

“…As a result, chromosomes trapped in micronuclei are prone to incomplete replication, DNA breaks, and chromosomal shattering leading to complex rearrangements (i.e., chromothripsis) ( Crasta et al, 2012 ; Hatch et al, 2013 ; Zhang et al, 2015 ; Liu et al, 2018 ; Tang et al, 2022 ). There is evidence micronucleus instability can cause punctuated bursts of numerical and structural chromosomal alterations within a few cell divisions and promote inflammation, epithelial-to-mesenchymal transition, and metastasis ( Mackenzie et al, 2017 ; Bakhoum et al, 2018 ; Umbreit et al, 2020 ), but we are still learning about the cellular events leading to micronuclei rupture in normal and cancer cells ( Sepaniac et al, 2021 ; Agustinus et al, 2022 ; Mammel et al, 2022 ; Papathanasiou et al, 2022 ). Chromothripsis is more frequent in WGD+ than WGD− cancers ( Notta et al, 2016 ; Cortés-Ciriano et al, 2020 ), likely reflecting an increase in both the rates and tolerance of genomic alterations in tetraploid cells.…”

Chromosome Inequality: Causes and Consequences of Non-Random Segregation Errors in Mitosis and Meiosis

“…Interestingly, chromosomes that end up in micronuclei have a higher probability of improperly segregating in the following mitoses [ 41 , 42 ]. Around half of micronuclei undergo membrane rupture [ 42 ], causing defective replication, inadequate nuclear protein import, epigenetic rewiring, exposure to cytosolic proteins [ 43 , 44 , 45 ], and missegregations during the next cell cycle [ 41 , 42 ]. Therefore, micronuclei catalyze the formation of chromosome-specific supernumerary and complex aneuploidies.…”

MCAK Inhibitors Induce Aneuploidy in Triple Negative Breast Cancer Models

“…Aneuploidy can be advantageous for tumors because it allows for heterogeneity, leading to favorable karyotypes that enhance proliferation, accelerate drug resistance, and/or reduce cell death [2,6,[69][70][71][72][73][74]. In addition, aberrant chromosome segregation can result in the formation of micronuclei, inducing several downstream consequences, including chromothrypsis, stimulation of the immune response, and epigenetic changes in daughter cells [2][3][4][5]31]. Too much aneuploidy can lead to lethality due to loss of genetic material.…”

“…CIN ultimately leads to aneuploidy in which the resulting daughter cells have an irregular number of chromosomes [2]. CIN can also induce the formation of micronuclei, which can be especially damaging, as micronuclei can undergo dramatic DNA rearrangements through chromothrypsis [3] and may result in epigenetic changes in daughter cell nuclei [4,5]. While CIN and aneuploidy are generally detrimental to cells, CIN can benefit tumor cells, as it can lead to tumor evolution by retention of favorable karyotypes [6,7].…”