Cell-type dependent enhancer binding of the EWS/ATF1 fusion gene in clear cell sarcomas

Shingo Komura, Kenji Ito, Sho Ohta, Tomoyo Ukai, Mio Kabata, Fumiaki Itakura, Katsunori Semi, Yutaka Matsuda, Kyoichi Hashimoto, Hirofumi Shibata, Masamitsu Sone, Norihide Jo, Kazuya Sekiguchi, Takatoshi Ohno, Haruhiko Akiyama, Katsuji Shimizu, Knut Woltjen, Manabu Ozawa, Junya Toguchida, Takuya Yamamoto and Yasuhiro Yamada ()
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Shingo Komura: Kyoto University
Kenji Ito: Kyoto University
Sho Ohta: University of Tokyo
Tomoyo Ukai: University of Tokyo
Mio Kabata: Kyoto University
Fumiaki Itakura: Kyoto University
Katsunori Semi: Kyoto University
Yutaka Matsuda: Kyoto University
Kyoichi Hashimoto: Kyoto University
Hirofumi Shibata: Kyoto University
Masamitsu Sone: Kyoto University
Norihide Jo: Kyoto University
Kazuya Sekiguchi: Kyoto University
Takatoshi Ohno: Gifu University Graduate School of Medicine
Haruhiko Akiyama: Gifu University Graduate School of Medicine
Katsuji Shimizu: Gifu Municipal Hospital
Knut Woltjen: Kyoto University
Manabu Ozawa: University of Tokyo
Junya Toguchida: Kyoto University
Takuya Yamamoto: Kyoto University
Yasuhiro Yamada: Kyoto University

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11745-1

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