Molecular Pathology Group, Tartu University, 50411 Tartu, Estonia.
Mol Immunol. 2011 Dec;49(3):518-26. doi: 10.1016/j.molimm.2011.09.022. Epub 2011 Oct 27.
Mutations in the AIRE gene cause autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), which is associated with autoimmunity towards several peripheral organs. The AIRE protein is almost exclusively expressed in medullary thymic epithelial cells (mTEC) and CpG methylation in the promoter of the AIRE gene has been suggested to control its tissue-specific expression pattern. We found that in human AIRE-positive medullary and AIRE-negative cortical epithelium, the AIRE promoter is hypomethylated, whereas in thymocytes, the promoter had high level of CpG methylation. Likewise, in mouse mTECs the AIRE promoter was uniformly hypomethylated. In the same vein, the AIRE promoter was hypomethylated in AIRE-negative thymic epithelial tumors (thymomas) and in several peripheral tissues. Our data are compatible with the notion that promoter hypomethylation is necessary but not sufficient for tissue-specific regulation of the AIRE gene. In contrast, a positive correlation between AIRE expression and histone H3 lysine 4 trimethylation, an active chromatin mark, was found in the AIRE promoter in human and mouse TECs.
AIRE 基因突变会导致自身免疫性多内分泌腺病念珠菌病外胚层营养不良（APECED），这种疾病与针对几个外周器官的自身免疫有关。AIRE 蛋白几乎只在髓质胸腺上皮细胞（mTEC）中表达，并且 AIRE 基因启动子中的 CpG 甲基化已被认为可以控制其组织特异性表达模式。我们发现，在人类 AIRE 阳性的髓质和 AIRE 阴性的皮质上皮中，AIRE 启动子呈低甲基化状态，而在胸腺细胞中，启动子的 CpG 甲基化水平很高。同样，在小鼠 mTEC 中，AIRE 启动子也呈均匀低甲基化状态。同样，在 AIRE 阴性的胸腺上皮肿瘤（胸腺瘤）和几个外周组织中，AIRE 启动子也呈低甲基化状态。我们的数据与以下观点一致，即启动子低甲基化是 AIRE 基因组织特异性调节所必需的，但不是充分的。相比之下，在人类和小鼠 TEC 中，AIRE 表达与组蛋白 H3 赖氨酸 4 三甲基化（一种活性染色质标记）呈正相关。
