A Histone Methyltransferase ESET Is Critical for T Cell Development
A Histone Methyltransferase ESET Is Critical for T Cell Development
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DOI：
10.4049/jimmunol.1502486
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发表时间：
2016-09
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通讯作者：
S. Takikita;Ryunosuke Muro;T. Takai;Takeshi Otsubo;Y. Kawamura;T. Dohi;Hiroyo Oda;M. Kitajima;K. Oshima;M. Hattori;T. Endo;Tetsuro Toyoda;J. Weis;Y. Shinkai;Harumi Suzuki
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作者：
S. Takikita;Ryunosuke Muro;T. Takai;Takeshi Otsubo;Y. Kawamura;T. Dohi;Hiroyo Oda;M. Kitajima;K. Oshima;M. Hattori;T. Endo;Tetsuro Toyoda;J. Weis;Y. Shinkai;Harumi Suzuki
ESET/SETDB1是主要的组蛋白甲基转移酶之一，可催化组蛋白3赖氨酸9 （H3K9）三甲基化。ESET对抑制胚胎干细胞中逆转录病毒因子的表达至关重要；然而，它在免疫系统中的作用尚不清楚。我们发现胸腺细胞特异性的ESET缺失导致T细胞发育受损，其中CD8谱系细胞受到的影响最为严重。CD8单阳性细胞凋亡增加，tcr诱导的ESET - / -胸腺细胞ERK活化受到严重抑制。对mRNA表达和H3K9三甲基化的全基因组综合分析显示，ESET调节胸腺细胞中许多基因的表达。其中，可抑制ERK活化的信号通路fc - γ riib在ESET−/−胸腺细胞中有强烈的异位表达。事实上，在ESET - / -小鼠胸腺细胞中，FcγRIIB的基因缺失挽救了受损的ERK激活，并部分恢复了有缺陷的阳性选择。因此，在ESET−/−小鼠中，T细胞发育受损部分是由于FcγRIIB的异常表达。总的来说，据我们所知，我们确定ESET是第一个在T细胞发育中起关键作用的三甲基化H3K9组蛋白甲基转移酶。
ESET/SETDB1, one of the major histone methyltransferases, catalyzes histone 3 lysine 9 (H3K9) trimethylation. ESET is critical for suppressing expression of retroviral elements in embryonic stem cells; however, its role in the immune system is not known. We found that thymocyte-specific deletion of ESET caused impaired T cell development, with CD8 lineage cells being most severely affected. Increased apoptosis of CD8 single-positive cells was observed, and TCR-induced ERK activation was severely inhibited in ESET−/− thymocytes. Genome-wide comprehensive analysis of mRNA expression and H3K9 trimethylation revealed that ESET regulates expression of numerous genes in thymocytes. Among them, FcγRIIB, whose signaling can inhibit ERK activation, was strongly and ectopically expressed in ESET−/− thymocytes. Indeed, genetic depletion of FcγRIIB in ESET−/− thymocytes rescued impaired ERK activation and partially restored defective positive selection in ESET−/− mice. Therefore, impaired T cell development in ESET−/− mice is partly due to the aberrant expression of FcγRIIB. Collectively, to our knowledge, we identify ESET as the first trimethylated H3K9 histone methyltransferase playing a crucial role in T cell development.