Watanabe Yukiko, Onodera Atsushi, Kanai Urara, Ichikawa Tomomi, Obata-Ninomiya Kazushige, Wada Tomoko, Kiuchi Masahiro, Iwamura Chiaki, Tumes Damon J, Shinoda Kenta, Yagi Ryoji, Motohashi Shinichiro, Hirahara Kiyoshi, Nakayama Toshinori
Departments of Immunology.
Medical Immunology, and.
Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):12829-34. doi: 10.1073/pnas.1321245111. Epub 2014 Aug 18.
Epigenetic modifications, such as posttranslational modifications of histones, play an important role in gene expression and regulation. These modifications are in part mediated by the Trithorax group (TrxG) complex and the Polycomb group (PcG) complex, which activate and repress transcription, respectively. We herein investigate the role of Menin, a component of the TrxG complex in T helper (Th) cell differentiation and show a critical role for Menin in differentiation and maintenance of Th17 cells. Menin(-/-) T cells do not efficiently differentiate into Th17 cells, leaving Th1 and Th2 cell differentiation intact in in vitro cultures. Menin deficiency resulted in the attenuation of Th17-induced airway inflammation. In differentiating Th17 cells, Menin directly bound to the Il17a gene locus and was required for the deposition of permissive histone modifications and recruitment of the RNA polymerase II transcriptional complex. Interestingly, although Menin bound to the Rorc locus, Menin was dispensable for the induction of Rorc expression and permissive histone modifications in differentiating Th17 cells. In contrast, Menin was required to maintain expression of Rorc in differentiated Th17 cells, indicating that Menin is essential to stabilize expression of the Rorc gene. Thus, Menin orchestrates Th17 cell differentiation and function by regulating both the induction and maintenance of target gene expression.
表观遗传修饰，如组蛋白的翻译后修饰，在基因表达和调控中发挥着重要作用。这些修饰部分由三胸复合物（TrxG）和多梳复合物（PcG）介导，它们分别激活和抑制转录。我们在此研究Menin（TrxG复合物的一个组成部分）在辅助性T（Th）细胞分化中的作用，并表明Menin在Th17细胞的分化和维持中起关键作用。Menin基因敲除（Menin(-/-)）的T细胞不能有效地分化为Th17细胞，而在体外培养中Th1和Th2细胞的分化不受影响。Menin缺乏导致Th17诱导的气道炎症减弱。在分化的Th17细胞中，Menin直接结合到Il17a基因位点，并且是允许性组蛋白修饰沉积和RNA聚合酶II转录复合物募集所必需的。有趣的是，尽管Menin结合到Rorc位点，但在分化的Th17细胞中，Menin对于Rorc表达的诱导和允许性组蛋白修饰是可有可无的。相反，Menin是维持分化的Th17细胞中Rorc表达所必需的，这表明Menin对于稳定Rorc基因的表达至关重要。因此，Menin通过调节靶基因表达的诱导和维持来协调Th17细胞的分化和功能。
