Cell state-dependent chromatin targeting in NUT carcinoma.
Cell state-dependent chromatin targeting in NUT carcinoma.
复制标题
NUT 癌中细胞状态依赖性染色质靶向。
DOI：
10.1093/genetics/iyad083
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发表时间：
2023
期刊：
影响因子：
3.3
通讯作者：
Kuroda,MitziI
中科院分区：
文献类型：
--
作者：
Alekseyenko,ArtyomA;Zee,BarryM;Dhoondia,Zuzer;Kang,Hyuckjoon;Makofske,JessicaL;Kuroda,MitziI
异常转录编程和染色质失调是大多数癌症的常见现象。无论是通过紊乱的细胞信号传导还是环境损伤，所产生的致癌表型通常表现为未分化细胞生长特征性的转录变化。在这里，我们分析了靶向的致癌融合蛋白，BRD 4-NUT，由2个正常独立的染色质调节。这种融合导致形成大的高度乙酰化的基因组区域或巨蛋白，c-MYC的错误调节，以及鳞状细胞起源的侵袭性癌。我们以前的工作揭示了不同NUT癌患者细胞系中很大程度上不同的megadomain位置。为了评估这是否是由于个体基因组序列或表观遗传细胞状态的变化，我们在人干细胞模型中表达BRD 4-NUT，并发现当将多能状态的细胞与沿着中胚层谱系诱导后的相同细胞系进行比较时，巨核蛋白以不同的模式形成。因此，我们的工作暗示初始细胞状态是BRD 4-NUT巨肌群位置的关键因素。这些结果，连同我们对患者细胞系中c-MYC蛋白-蛋白相互作用的分析，与NUT癌潜在的染色质失调级联反应一致。
Aberrant transcriptional programming and chromatin dysregulation are common to most cancers. Whether by deranged cell signaling or environmental insult, the resulting oncogenic phenotype is typically manifested in transcriptional changes characteristic of undifferentiated cell growth. Here we analyze targeting of an oncogenic fusion protein, BRD4-NUT, composed of 2 normally independent chromatin regulators. The fusion causes the formation of large hyperacetylated genomic regions or megadomains, mis-regulation ofc-MYC,and an aggressive carcinoma of squamous cell origin. Our previous work revealed largely distinct megadomain locations in different NUT carcinoma patient cell lines. To assess whether this was due to variations in individual genome sequences or epigenetic cell state, we expressed BRD4-NUT in a human stem cell model and found that megadomains formed in dissimilar patterns when comparing cells in the pluripotent state with the same cell line following induction along a mesodermal lineage. Thus, our work implicates initial cell state as the critical factor in the locations of BRD4-NUT megadomains. These results, together with our analysis of c-MYC protein-protein interactions in a patient cell line, are consistent with a cascade of chromatin misregulation underlying NUT carcinoma.