Transcriptional programs that control expression of the autoimmune regulator gene Aire
Transcriptional programs that control expression of the autoimmune regulator gene Aire
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DOI：
10.1038/ni.3638
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发表时间：
2017-02-01
影响因子：
30.5
通讯作者：
Abramson, Jakub
中科院分区：
文献类型：
--
作者：
Herzig, Yonatan;Nevo, Shir;Abramson, Jakub
Aire是一种转录调节因子，可诱导胸腺髓质上皮细胞（mTECs）中数千种编码组织限制性抗原（TRAs）的基因的混杂表达。虽然Aire的靶基因已被很好地表征，但调节其自身表达的转录程序仍然难以捉摸。在这里，我们全面分析了顺式作用和反式作用的调节机制，发现Aire基因座被全局染色质组织者CTCF隔离，并且在不表达Aire的细胞和组织中高度甲基化。然而，在mTECs中，CTCF的同时驱逐，外显子2和近端启动子的特异性去甲基化，以及几种转录激活因子的协调作用，包括Irf4，Irf8，Tbx21，Tcf7和Ctcfl，这些转录激活因子作用于Aire基因座中的mTECs特异性可及区域，从而促进了Aire的表达。
Aire is a transcriptional regulator that induces promiscuous expression of thousands of genes encoding tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs). While the target genes of Aire are well characterized, the transcriptional programs that regulate its own expression have remained elusive. Here we comprehensively analyzed both cis-acting and trans-acting regulatory mechanisms and found that the Aire locus was insulated by the global chromatin organizer CTCF and was hypermethylated in cells and tissues that did not express Aire. In mTECs, however, Aire expression was facilitated by concurrent eviction of CTCF, specific demethylation of exon 2 and the proximal promoter, and the coordinated action of several transcription activators, including Irf4, Irf8, Tbx21, Tcf7 and Ctcfl, which acted on mTEC-specific accessible regions in the Aire locus.