The RNA exosome contributes to gene expression regulation during stem cell differentiation [PRO-Seq 2]

Gene expression programs change during cellular transitions. It is well established that a network of transcription factors and chromatin modifiers regulate RNA levels during embryonic stem cell (ESC) differentiation, but the full impact of post-transcriptional processes remains elusive. While cytoplasmic RNA turnover mechanisms have been implicated in differentiation, the contribution of nuclear RNA decay has not been investigated. Here, we differentiate mouse ESCs, depleted for the ribonucleolytic RNA exosome, into embryoid bodies to determine to which degree RNA abundance in the two states can be attributed to changes in transcription vs. RNA decay by the exosome. As a general observation, we find that exosome depletion mainly leads to the stabilization of RNAs from lowly transcribed loci, including several protein-coding genes. Depletion of the nuclear exosome cofactor RBM7 leads to similar effects. In particular, transcripts that are differentially expressed between states tend to be more exosome sensitive in the state where expression is low. We conclude that the RNA exosome contributes to down-regulation of transcripts with disparate expression, often in conjunction with transcriptional down-regulation.

细胞转变过程中，基因表达程序会发生动态改变。已有研究证实，胚胎干细胞（ESC）分化过程中，转录因子与染色质修饰因子构成的调控网络可影响RNA水平，但转录后过程的整体调控效应仍有待明确。尽管已有研究表明细胞质RNA周转机制参与了分化调控，但细胞核RNA降解途径的具体贡献尚未被探究。
本研究将敲低核糖核酸酶RNA外切体（RNA exosome）的小鼠胚胎干细胞诱导为拟胚体，以此探究两种细胞状态下的RNA丰度，在多大程度上可归因于转录变化，或是RNA外切体介导的RNA降解。
整体观测结果显示，RNA外切体敲低主要会稳定低转录基因座的RNA分子，其中包含多个蛋白质编码基因。细胞核RNA外切体辅助因子RBM7的敲低也会产生类似的效应。尤为值得注意的是，不同细胞状态间的差异表达转录本，在其表达水平较低的细胞状态中，往往对RNA外切体更为敏感。
综上，RNA外切体可参与介导差异表达转录本的下调过程，且通常与转录下调协同发挥调控作用。