TY - JOUR
T1 - Identification of a genomic enhancer that enforces proper apoptosis induction in thymic negative selection
AU - Hojo, Miki Arai
AU - Masuda, Kyoko
AU - Hojo, Hiroaki
AU - Nagahata, Yosuke
AU - Yasuda, Keiko
AU - Ohara, Daiya
AU - Takeuchi, Yusuke
AU - Hirota, Keiji
AU - Suzuki, Yutaka
AU - Kawamoto, Hiroshi
AU - Kawaoka, Shinpei
N1 - Funding Information:
We thank Dr. Thomas. N. Sato (T.N.S), the director of The TNS BioMEC-X Laboratories, ATR, and JST ERATO Sato Live Bio-forecasting project, for supporting all aspects of the study. We thank Tomoko Kuroda, Tomoko Ninomiya, Hitomi Anabuki, Satsuki Endo, Fumihiko Sagawa, Satoshi Kozawa, Terumi Horiuchi, and Kiyomi Imamura for technical assistance. We thank Ryoko Takahashi, Erika Kojima, and Toshiya Morie for administrative assistance. We are thankful to Dr. Pieter Bas Kwak and Dr. Bryce Nelson for critically reading the manuscript. We also thank Dr. Kosuke Yusa and Dr. Takeshi Watanabe for providing insightful comments on the manuscript. Dr. Thomas. N. Sato and the members of the TNS BioMEC-X Laboratories provided insightful comments on the manuscript. This work was supported by JST ERATO (to S.K. via T.N.S; JPMJER1303), JSPS KAKENHI (26890030, 15H01478, 18K15409, and 18H04810: S.K.), The Uehara Memorial Foundation (S.K.), The Shimizu Foundation for Immunology and Neuroscience Grant for 2018 (S.K) and Japan Foundation for Applied Enzymology (S.K.).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - During thymic negative selection, autoreactive thymocytes carrying T cell receptor (TCR) with overtly strong affinity to self-MHC/self-peptide are removed by Bim-dependent apoptosis, but how Bim is specifically regulated to link TCR activation and apoptosis induction is unclear. Here we identify a murine T cell-specific genomic enhancer EBAB (Bub1-Acoxl-Bim), whose deletion leads to accumulation of thymocytes expressing high affinity TCRs. Consistently, EBAB knockout mice have defective negative selection and fail to delete autoreactive thymocytes in various settings, with this defect accompanied by reduced Bim expression and apoptosis induction. By contrast, EBAB is dispensable for maintaining peripheral T cell homeostasis via Bim-dependent pathways. Our data thus implicate EBAB as an important, developmental stage-specific regulator of Bim expression and apoptosis induction to enforce thymic negative selection and suppress autoimmunity. Our study unravels a part of genomic enhancer codes that underlie complex and context-dependent gene regulation in TCR signaling.
AB - During thymic negative selection, autoreactive thymocytes carrying T cell receptor (TCR) with overtly strong affinity to self-MHC/self-peptide are removed by Bim-dependent apoptosis, but how Bim is specifically regulated to link TCR activation and apoptosis induction is unclear. Here we identify a murine T cell-specific genomic enhancer EBAB (Bub1-Acoxl-Bim), whose deletion leads to accumulation of thymocytes expressing high affinity TCRs. Consistently, EBAB knockout mice have defective negative selection and fail to delete autoreactive thymocytes in various settings, with this defect accompanied by reduced Bim expression and apoptosis induction. By contrast, EBAB is dispensable for maintaining peripheral T cell homeostasis via Bim-dependent pathways. Our data thus implicate EBAB as an important, developmental stage-specific regulator of Bim expression and apoptosis induction to enforce thymic negative selection and suppress autoimmunity. Our study unravels a part of genomic enhancer codes that underlie complex and context-dependent gene regulation in TCR signaling.
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U2 - 10.1038/s41467-019-10525-1
DO - 10.1038/s41467-019-10525-1
M3 - Article
C2 - 31197149
AN - SCOPUS:85067313239
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2603
ER -