Abstract：
Previous studies towards reduced oxygen availability have mostly focused on changes in total mRNA expression, neglecting underlying transcriptional and post-transcriptional events. Therefore, we generated a comprehensive overview of hypoxia-induced changes in total mRNA expression, global de novo transcription, and mRNA stability in monocytic THP-1 cells. Since hypoxic episodes often persist for prolonged periods, we further compared the adaptation to acute and chronic hypoxia. While total mRNA changes correlated well with enhanced transcription during short-term hypoxia, mRNA destabilization gained importance under chronic conditions. Reduced mRNA stability not only added to a compensatory attenuation of immune responses, but also, most notably, to the reduction in nuclear-encoded mRNAs associated with various mitochondrial functions. These changes may prevent the futile production of new mitochondria under conditions where mitochondria cannot exert their full metabolic function and are indeed actively removed by mitophagy. The post-transcriptional mode of regulation might further allow for the rapid recovery of mitochondrial capacities upon reoxygenation. Our results provide a comprehensive resource of functional mRNA expression dynamics and underlying transcriptional and post-transcriptional regulatory principles during the adaptation to hypoxia. Furthermore, we uncover that RNA stability regulation controls mitochondrial functions in the context of hypoxia.
摘要：
以前关于降低氧气利用率的研究主要集中在总mRNA表达的变化上，忽略潜在的转录和转录后事件。因此,我们对缺氧诱导的总mRNA表达变化进行了全面概述，全局从头转录，和单核细胞THP-1细胞中的mRNA稳定性。由于缺氧事件通常会持续很长时间，我们进一步比较了对急性和慢性缺氧的适应。虽然在短期缺氧期间，总mRNA的变化与转录增强密切相关，mRNA不稳定在慢性条件下变得重要。降低的mRNA稳定性不仅增加了免疫反应的补偿性减弱，而且,最值得注意的是,与各种线粒体功能相关的核编码mRNA的减少。这些变化可能会在线粒体不能发挥其全部代谢功能并且确实被线粒体自噬主动清除的条件下阻止新线粒体的徒劳产生。转录后调节模式可能进一步允许线粒体能力在复氧后的快速恢复。我们的结果提供了在适应缺氧过程中功能性mRNA表达动力学以及潜在的转录和转录后调控原理的综合资源。此外，我们发现RNA稳定性调节在缺氧的情况下控制线粒体功能。
