Institute for Frontier Life and Medical Sciences, Kyoto University

Identification of a genomic enhancer that enforces proper apoptosis induction in thymic negative selection

Miki Arai Hojo1, Kyoto Masuda2, Hiroaki Hojo2, Yosuke Nagahata2, Keiko Yasuda2, Daiya Ohara2, Yusuke Takeuchi2, Keiji Hirota2, Yutaka Suzuki1, Hiroshi Kawamoto2, Shinpei Kawaoka2

1The University of Tokyo
2Instutite for Frontier Life and Medical Sciences, Kyoto University

 

Identification of a genomic enhancer that enforces proper apoptosis induction in thymic negative selection.

Nature Communications (2019) doi: 10.1038/s41467-019-10525-1.

Abstract

Here we identify a genomic enhancer that is required for elimination of autoreacitive T cells in the thymus.
    In the thymus, the process called negative selection depletes thymocytes expressing TCRs that strongly recognize self-antigens as autoreactive T cells. Pro-apoptotic Bim plays a role in thymic negative selection: TCR signal activates expression of Bim and Bim KO fails to achieve negative selection. However, it has been unclear how TCR signal is linked to Bim expression, and whether Bim up-regulation during TCR activation is necessary for thymic negative selection.
    Genomic enhancers are non-coding DNA elements that determine spatio-temporal gene expression patterns. In the current study, via epigenome analyses and CRISPR-Cas9 based enhancer knockout approach, we find a genomic enhancer whose deletion results in accumulation of autoreactive thymocytes and insufficient up-regulation of Bim during thymic negative selection. Intriguingly, a physiological role of the enhancer appears highly dedicated to thymic negative selection while dispensable for other Bim-dependent biological processes.
    Our study provides a novel insight into how thymocytes distinguish self through the enhancer-mediated mechanism. In addition, this study is an example of utilizing enhancer knockout to ablate specific gene regulation, enabling us to dissect physiological importance of single gene regulation in vivo.

 

 

Graphical summary

We identify a genomic enhancer that is required for TCR signal dependent Bim-activation and thymic negative selection.