Genomic instability is an early event driving chromatin organization and “escape” from oncogene-induced senescence

Oncogene-induced senescence (OIS) is an inherent and important tumor suppressor mechanism. However, if not timely removed via immune surveillance, senescent cells will also present a detrimental side. Although this has mostly been attributed to the senescence-associated-secretory-phenotype (SASP) of these cells, we recently suggested that “escape” from the senescent state represents another unfavorable outcome. Here, we exploit genomic and functional data from a prototypical human epithelial cell model carrying an inducible CDC6 oncogene to identify an early-acquired recurrent chromosomal inversion, which harbors a locus encoding the circadian transcription factor BHLHE40. This inversion alone suffices for activation of BHLHE40 upon CDC6 induction and for driving cell cycle re-entry and malignant transformation. In summary, we provide strong evidence in support of genomic instability underlying “escape” from oncogene-induced senescence. In situ Hi-C performed in two states (“OFF” and “Bypass”) of a single cell-derived HBEC clone carrying a CRISPR-generated >3-Mbp inversion on chr3 that encompasses the BHLHE40 gene locus

癌基因诱导的衰老（Oncogene-induced senescence, OIS）是一种固有且关键的肿瘤抑制机制。然而，若无法通过免疫监视及时清除衰老细胞，这类细胞亦会产生有害的负面效应。尽管该现象大多被归因于细胞的衰老相关分泌表型（senescence-associated secretory phenotype, SASP），但我们的最新研究提出，从衰老状态中"逃逸"是另一类不利结局。本研究利用携带可诱导CDC6癌基因的典型人类上皮细胞模型的基因组与功能数据，鉴定出一种早期获得的复发性染色体倒位，该倒位包含一个编码节律转录因子BHLHE40的基因座。仅该染色体倒位即可在CDC6诱导时激活BHLHE40的表达，并驱动细胞周期再进入与恶性转化。综上，我们为"基因组不稳定性介导癌基因诱导的衰老逃逸"这一论点提供了强有力的证据。本研究还针对两种状态（"OFF"与"Bypass"）下的单细胞来源人类支气管上皮细胞（Human Bronchial Epithelial Cells, HBEC）克隆开展了原位Hi-C（in situ Hi-C）实验，该克隆在3号染色体上带有经CRISPR编辑的、覆盖BHLHE40基因座的大于3兆碱基对的染色体倒位。