Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA.
Graduate Field of Genetics, Genomics, and Development, Cornell University, Ithaca, New York 14853, USA.
RNA. 2022 Jul;28(7):947-971. doi: 10.1261/rna.078918.121. Epub 2022 May 5.
The poly(A) tail enhances translation and transcript stability, and tail length is under dynamic control during cell state transitions. Tail regulation plays essential roles in translational timing and fertilization in early development, but poly(A) tail dynamics have not been fully explored in post-embryonic systems. Here, we examined the landscape and impact of tail length control during macrophage activation. Upon activation, more than 1500 mRNAs, including proinflammatory genes, underwent distinctive changes in tail lengths. Increases in tail length correlated with mRNA levels regardless of transcriptional activity, and many mRNAs that underwent tail extension encode proteins necessary for immune function and post-transcriptional regulation. Strikingly, we found that , whose protein product destabilizes target transcripts, undergoes tail extension. Our analyses indicate that many mRNAs undergoing tail lengthening are, in turn, degraded by elevated levels of ZFP36, constituting a post-transcriptional feedback loop that ensures transient regulation of transcripts integral to macrophage activation. Taken together, this study establishes the complexity, relevance, and widespread nature of poly(A) tail dynamics, and the resulting post-transcriptional regulation during macrophage activation.
多聚（A）尾增强翻译和转录本稳定性，并且在细胞状态转变过程中，尾长处于动态控制之下。在早期发育的翻译定时和受精过程中，尾巴调控起着至关重要的作用，但在胚胎后系统中，多聚（A）尾的动态尚未得到充分探索。在这里，我们研究了巨噬细胞激活过程中尾巴长度控制的情况和影响。在激活过程中，超过 1500 个 mRNA，包括促炎基因，在尾巴长度上发生了独特的变化。尾巴长度的增加与 mRNA 水平相关，而不管转录活性如何，并且许多经历尾巴延伸的 mRNAs 编码对免疫功能和转录后调控至关重要的蛋白质。引人注目的是，我们发现 ，其蛋白产物会使靶转录本不稳定，经历尾巴延伸。我们的分析表明，许多经历尾巴延长的 mRNAs 会被水平升高的 ZFP36 降解，从而构成一个转录后反馈回路，确保对巨噬细胞激活过程中重要的转录本进行短暂调控。总之，这项研究确立了多聚（A）尾动力学的复杂性、相关性和广泛性质，以及在巨噬细胞激活过程中的后续转录调控。
