非编码 RNA circBtnl1 通过破坏 Atf4 mRNA 的稳定性来抑制肠道干细胞的自我更新。
Noncoding RNA circBtnl1 suppresses self-renewal of intestinal stem cells via disruption of Atf4 mRNA stability.
机构信息
Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
出版信息
EMBO J. 2023 Mar 15;42(6):e112039. doi: 10.15252/embj.2022112039. Epub 2023 Jan 30.
Intestinal stem cells (ISCs) at the crypt base are responsible for the regeneration of the intestinal epithelium. However, how ISC self-renewal is regulated still remains unclear. Here we identified a circular RNA, circBtnl1, that is highly expressed in ISCs. Loss of circBtnl1 in mice enhanced ISC self-renewal capacity and epithelial regeneration, without changes in mRNA and protein levels of its parental gene Btnl1. Mechanistically, circBtnl1 and Atf4 mRNA competitively bound the ATP-dependent RNA helicase Ddx3y to impair the stability of Atf4 mRNA in wild-type ISCs. Furthermore, ATF4 activated Sox9 transcription by binding to its promoter via a unique motif, to enhance the self-renewal capacity and epithelial regeneration of ISCs. In contrast, circBtnl1 knockout promoted Atf4 mRNA stability and enhanced ATF4 expression, which caused Sox9 transcription to potentiate ISC stemness. These data indicate that circBtnl1-mediated Atf4 mRNA decay suppresses Sox9 transcription that negatively modulates self-renewal maintenance of ISCs.
肠干细胞（ISCs）位于隐窝底部，负责肠道上皮的再生。然而，ISC 自我更新是如何调节的仍不清楚。在这里，我们鉴定了一种高度表达于 ISCs 的环状 RNA，circBtnl1。在小鼠中敲除 circBtnl1 增强了 ISC 的自我更新能力和上皮再生，而其亲本基因 Btnl1 的 mRNA 和蛋白水平没有变化。在机制上，circBtnl1 和 Atf4 mRNA 竞争性结合 ATP 依赖的 RNA 解旋酶 Ddx3y，从而损害野生型 ISC 中 Atf4 mRNA 的稳定性。此外，ATF4 通过结合其启动子上的独特基序激活 Sox9 转录，以增强 ISC 的自我更新能力和上皮再生。相比之下，circBtnl1 敲除促进了 Atf4 mRNA 的稳定性，并增强了 ATF4 的表达，从而导致 Sox9 转录增强 ISC 的干性。这些数据表明，circBtnl1 介导的 Atf4 mRNA 降解抑制 Sox9 转录，从而负调控 ISC 的自我更新维持。
Zotero 插件