Transcriptional heterogeneity due to plasticity of the epigenetic state of chromatin contributes to tumour evolution, metastasis and drug resistance^1,2,3. However, the mechanisms that cause this epigenetic variation are incompletely understood. Here we identify micronuclei and chromosome bridges, aberrations in the nucleus common in cancer^4,5, as sources of heritable transcriptional suppression. Using a combination of approaches, including long-term live-cell imaging and same-cell single-cell RNA sequencing (Look-Seq2), we identified reductions in gene expression in chromosomes from micronuclei. With heterogeneous penetrance, these changes in gene expression can be heritable even after the chromosome from the micronucleus has been re-incorporated into a normal daughter cell nucleus. Concomitantly, micronuclear chromosomes acquire aberrant epigenetic chromatin marks. These defects may persist as variably reduced chromatin accessibility and reduced gene expression after clonal expansion from single cells. Persistent transcriptional repression is strongly associated with, and may be explained by, markedly long-lived DNA damage. Epigenetic alterations in transcription may therefore be inherently coupled to chromosomal instability and aberrations in nuclear architecture.

由于染色质表观遗传状态的可塑性而导致的转录异质性有助于肿瘤的进化、转移和耐药性^1,2,3。然而，导致这种表观遗传变异的机制尚不完全清楚。在这里，我们将微核和染色体桥、癌症中常见的细胞核畸变^4,5确定为可遗传转录抑制的来源。通过结合多种方法，包括长期活细胞成像和同细胞单细胞 RNA 测序 (Look-Seq2)，我们发现微核染色体中基因表达的减少。由于外显率异质，即使来自微核的染色体已重新掺入正常子细胞核中，这些基因表达的变化也可以遗传。与此同时，微核染色体获得异常的表观遗传染色质标记。这些缺陷可能会随着单细胞克隆扩增后染色质可及性的不同程度降低和基因表达的降低而持续存在。持续的转录抑制与显着长寿命的 DNA 损伤密切相关，并且可以通过这种损伤来解释。因此，转录中的表观遗传改变可能本质上与染色体不稳定性和核结构畸变相关。