Highly connected 3D chromatin networks established by an oncogenic fusion protein shape tumor cell identity.
Highly connected 3D chromatin networks established by an oncogenic fusion protein shape tumor cell identity.
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由致癌融合蛋白建立的高度连接的3D染色质网络形成肿瘤细胞身份。
DOI：
10.1126/sciadv.abo3789
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发表时间：
2023-03-31
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
作者：
在胚胎发育中观察到的细胞命运转变涉及三维基因组组织的变化，提供了适当的谱系说明。类似的事件是否发生在肿瘤细胞内，并导致癌症的进化，在很大程度上仍未被研究。我们在儿童癌症尤因肉瘤中模拟了这一过程，并研究了与致癌融合蛋白EWS-FLI1相关的高分辨率环和大规模核构象变化。我们发现，肿瘤细胞中的染色质相互作用主要由以EWS-FLI1结合位点为中心的高度连接的环枢纽控制，这些环枢纽直接控制连接的增强子和启动子的活性，以建立致癌表达程序。相反，EWS-FLI1的缺失导致这些环网络的解体，并通过建立新的环模式和与在间质干细胞（候选尤文氏肉瘤祖细胞）中观察到的相匹配的大尺度室结构而广泛地进行核重组。我们的数据表明，癌细胞中核组织的主要结构特征可以依赖于单个癌基因，并且很容易逆转以重建潜在的分化程序。一种致癌转录因子对细胞核组织的重塑决定了肿瘤细胞的身份。
Cell fate transitions observed in embryonic development involve changes in three-dimensional genomic organization that provide proper lineage specification. Whether similar events occur within tumor cells and contribute to cancer evolution remains largely unexplored. We modeled this process in the pediatric cancer Ewing sarcoma and investigated high-resolution looping and large-scale nuclear conformation changes associated with the oncogenic fusion protein EWS-FLI1. We show that chromatin interactions in tumor cells are dominated by highly connected looping hubs centered on EWS-FLI1 binding sites, which directly control the activity of linked enhancers and promoters to establish oncogenic expression programs. Conversely, EWS-FLI1 depletion led to the disassembly of these looping networks and a widespread nuclear reorganization through the establishment of new looping patterns and large-scale compartment configuration matching those observed in mesenchymal stem cells, a candidate Ewing sarcoma progenitor. Our data demonstrate that major architectural features of nuclear organization in cancer cells can depend on single oncogenes and are readily reversed to reestablish latent differentiation programs. Remodeling of nuclear organization by an oncogenic transcription factor determines tumor cell identity.
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