Department of Developmental & Stem Cells Biology, Institut Pasteur, CNRS URA 2578, Laboratoire de Génétique Moléculaire Murine, Paris, FranceUniversité Pierre et Marie Curie, Cellule Pasteur UPMC, Paris, France.
Department of Developmental & Stem Cells Biology, Institut Pasteur, CNRS URA 2578, Laboratoire de Génétique Moléculaire Murine, Paris, France.
Diabetes. 2014 Jun;63(6):2148-57. doi: 10.2337/db13-1702. Epub 2014 Feb 11.
The circadian rhythm-related aryl hydrocarbon receptor nuclear translocator-like 2 (Arntl2) gene has been identified as a candidate gene for the murine type 1 diabetes locus Idd6.3. Previous studies suggested a role in expansion of CD4(+)CD25(-) T cells, and this then creates an imbalance in the ratio between T-effector and CD4(+)CD25(+) T-regulator cells. Our transcriptome analyses identify the interleukin 21 (IL21) gene (Il21) as a direct target of ARNTL2. ARNTL2 binds in an allele-specific manner to the RNA polymerase binding site of the Il21 promoter and inhibits its expression in NOD.C3H congenic mice carrying C3H alleles at Idd6.3. IL21 is known to promote T-cell expansion, and in agreement with these findings, mice with C3H alleles at Idd6.3 produce lower numbers of CD4(+)IL21(+) and CD4(+) and CD8(+) T cells compared with mice with NOD alleles at Idd6.3. Our results describe a novel and rather unexpected role for Arntl2 in the immune system that lies outside of its predicted function in circadian rhythm regulation.
昼夜节律相关的芳香烃受体核转位蛋白样 2（Arntl2）基因已被确定为小鼠 1 型糖尿病 Idd6.3 位点的候选基因。先前的研究表明其在 CD4(+)CD25(-)T 细胞扩增中起作用，从而导致 T 效应细胞和 CD4(+)CD25(+)T 调节细胞之间的比例失衡。我们的转录组分析确定白细胞介素 21（IL21）基因（Il21）是 ARNTL2 的直接靶标。ARNTL2 以等位基因特异性的方式结合到 Il21 启动子的 RNA 聚合酶结合位点，并抑制 NOD.C3H 同基因小鼠中 Idd6.3 处携带 C3H 等位基因的 Il21 表达。已知 IL21 可促进 T 细胞扩增，与这些发现一致的是，在 Idd6.3 处具有 NOD 等位基因的小鼠产生的 CD4(+)IL21(+)和 CD4(+)和 CD8(+)T 细胞数量低于在 Idd6.3 处具有 C3H 等位基因的小鼠。我们的结果描述了 Arntl2 在免疫系统中的一个新的、相当意外的作用，它位于其在昼夜节律调节中的预期功能之外。
