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.

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.