Kakugawa Kiyokazu, Kojo Satoshi, Tanaka Hirokazu, Seo Wooseok, Endo Takaho A, Kitagawa Yohko, Muroi Sawako, Tenno Mari, Yasmin Nighat, Kohwi Yoshinori, Sakaguchi Shimon, Kowhi-Shigematsu Terumi, Taniuchi Ichiro
Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences (IMS), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
Cell Rep. 2017 May 9;19(6):1176-1188. doi: 10.1016/j.celrep.2017.04.038.
T cell receptor (TCR) signaling by MHC class I and II induces thymocytes to acquire cytotoxic and helper fates via the induction of Runx3 and ThPOK transcription factors, respectively. The mechanisms by which TCR signaling is translated into transcriptional programs for each cell fate remain elusive. Here, we show that, in post-selection thymocytes, a genome organizer, SATB1, activates genes for lineage-specifying factors, including ThPOK, Runx3, CD4, CD8, and Treg factor Foxp3, via regulating enhancers in these genes in a locus-specific manner. Indeed, SATB1-deficient thymocytes are partially re-directed into inappropriate T lineages after both MHC class I- and II-mediated selection, and they fail to generate NKT and Treg subsets. Despite its essential role in activating enhancers for the gene encoding ThPOK in TCR-signaled thymocytes, SATB1 becomes dispensable for maintaining ThPOK in CD4 T cells. Collectively, our findings demonstrate that SATB1 shapes the primary T cell pool by directing lineage-specific transcriptional programs in the thymus.
MHC I类和II类分子介导的T细胞受体（TCR）信号传导分别通过诱导Runx3和ThPOK转录因子，促使胸腺细胞获得细胞毒性和辅助性细胞命运。TCR信号如何转化为每种细胞命运的转录程序，其机制仍不清楚。在此，我们表明，在选择后的胸腺细胞中，一种基因组组织者SATB1通过以位点特异性方式调控这些基因中的增强子，激活包括ThPOK、Runx3、CD4、CD8和调节性T细胞（Treg）因子Foxp3在内的谱系特异性因子的基因。事实上，在MHC I类和II类介导的选择后，SATB1缺陷的胸腺细胞会部分重定向到不适当的T细胞谱系，并且无法产生自然杀伤T细胞（NKT）和Treg亚群。尽管SATB1在TCR信号传导的胸腺细胞中对激活编码ThPOK的基因的增强子起着至关重要的作用，但在CD4 T细胞中维持ThPOK表达时，SATB1变得不再必要。总的来说，我们的研究结果表明，SATB1通过指导胸腺中谱系特异性转录程序来塑造初始T细胞库。
