Cell-type dependent enhancer binding of the EWS/ATF1 fusion gene in clear cell sarcomas
Cell-type dependent enhancer binding of the EWS/ATF1 fusion gene in clear cell sarcomas
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DOI：
10.1038/s41467-019-11745-1
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发表时间：
2019-09-05
影响因子：
16.6
通讯作者：
Yamada, Yasuhiro
中科院分区：
文献类型：
--
作者：
Komura, Shingo;Ito, Kenji;Yamada, Yasuhiro
透明细胞肉瘤（CCS）是一种罕见的由EWS/ATF1融合基因引起的软组织肉瘤。在这里，我们从EWS/ atf1可控的小鼠CCS细胞中建立了诱导多能干细胞（iPSCs），这些细胞含有肉瘤相关的遗传异常。肉瘤- ipsc小鼠在EWS/ATF1诱导后立即发生继发性肉瘤，但仅在软组织中发生。EWS/ATF1表达在大多数肉瘤- ipsc小鼠细胞类型中诱导癌基因诱导的衰老，但在肉瘤细胞中阻止其发生。我们发现周围神经中表达tppp3的细胞是这些肉瘤的起源细胞。我们在CCS细胞中发现了EWS/ATF1在增强区域的细胞类型特异性募集。最后，这些增强子的表观遗传沉默通过改变EWS/ATF1结合诱导衰老并抑制CCS细胞生长。总之，我们提出对过早衰老的不同反应是癌症发展的细胞类型特异性的基础。
Clear cell sarcoma (CCS) is a rare soft tissue sarcoma caused by the EWS/ATF1 fusion gene. Here, we established induced pluripotent stem cells (iPSCs) from EWS/ATF1-controllable murine CCS cells harboring sarcoma-associated genetic abnormalities. Sarcoma-iPSC mice develop secondary sarcomas immediately after EWS/ATF1 induction, but only in soft tissue. EWS/ATF1 expression induces oncogene-induced senescence in most cell types in sarcoma-iPSC mice but prevents it in sarcoma cells. We identify Tppp3-expressing cells in peripheral nerves as a cell-of-origin for these sarcomas. We show cell type-specific recruitment of EWS/ATF1 to enhancer regions in CCS cells. Finally, epigenetic silencing at these enhancers induces senescence and inhibits CCS cell growth through altered EWS/ATF1 binding. Together, we propose that distinct responses to premature senescence are the basis for the cell type-specificity of cancer development.