Glucocorticoids (Gcs) potently inhibit inflammation, and regulate liver energy metabolism, often acting in a hypoxic environment. We now show hypoxic conditions open a specific GR cistrome, and prevent access of GR to part of the normoxic GR cistrome. Motif analysis identified enrichment of KLF4 binding sites beneath those peaks of GR binding exclusive to normoxia, implicating KLF4 as a pioneer, or co-factor under these conditions. Hypoxia reduced KLF4 expression, however, knockdown of KLF4 did not impair GR recruitment. KLF4 is a known target of microRNAs 103 and 107, both of which are induced by hypoxia. Expression of mimics to either microRNA103, or microRNA107 inhibited GR transactivation of normoxic target genes, thereby replicating the hypoxic effect. Therefore, studies in hypoxia reveal that microRNAs 103 and 107 are potent regulators of GR function. We have now identified a new pathway linking hypoxia through microRNAs 103 and 107 to regulation of GR function.

糖皮质激素 (Gcs) 有效抑制炎症，调节肝脏能量代谢，通常在缺氧环境中起作用。我们现在显示缺氧条件会打开特定的 GR 池，并阻止 GR 进入常氧 GR 池的一部分。基序分析确定了 KLF4 结合位点的富集，这些结合位点位于常氧区独有的 GR 结合峰下方，暗示 KLF4 是这些条件下的先驱或辅助因素。缺氧降低了 KLF4 的表达，然而，KLF4 的敲低并没有损害 GR 的招募。KLF4 是 microRNAs 103 和 107 的已知靶标，两者都是由缺氧诱导的。对 microRNA103 或 microRNA107 的模拟物的表达抑制了常氧靶基因的 GR 反式激活，从而复制了缺氧效应。所以，缺氧研究表明，microRNA 103 和 107 是 GR 功能的有效调节剂。我们现在已经确定了一种通过 microRNA 103 和 107 将缺氧与 GR 功能调节联系起来的新途径。