State Key Laboratory for Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Higher Education Mega Center, Guangzhou, 510006, China.
School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China.
Genome Res. 2018 Nov;28(11):1656-1663. doi: 10.1101/gr.231506.117. Epub 2018 Sep 18.
3' UTRs play important roles in the gene regulation network via their influence on mRNA stability, translational efficiency, and subcellular localization. For a given gene, 3' UTRs of different lengths generated by alternative polyadenylation (APA) may result in functional differences in regulation. The mechanistic details of how length changes of 3' UTRs alter gene function remain unclear. By combining APA sequencing and polysome profiling, we observed that mRNA isoforms with shorter 3' UTRs were bound with more polysomes in six cell lines but not in NIH3T3 cells, suggesting that changing 3' UTRs to shorter isoforms may lead to a higher gene translational efficiency. By interfering with the expression of TNRC6A and analyzing AGO2-PAR-CLIP data, we revealed that the APA effect on translational efficiency was mainly regulated by miRNAs, and this regulation was cell cycle dependent. The discrepancy between NIH3T3 and other cell lines was due to contact inhibition of NIH3T3. Thus, the crosstalk between APA and miRNAs may be needed for the regulation of protein translational efficiency.
3'UTR 通过影响 mRNA 稳定性、翻译效率和亚细胞定位在基因调控网络中发挥重要作用。对于给定的基因，通过可变多聚腺苷酸化（APA）产生的不同长度的 3'UTR 可能导致调节的功能差异。3'UTR 长度变化如何改变基因功能的机制细节尚不清楚。通过结合 APA 测序和多核糖体谱分析，我们观察到在六种细胞系中，但在 NIH3T3 细胞中并非如此，较短 3'UTR 的 mRNA 异构体与更多的多核糖体结合，这表明将 3'UTR 改变为较短的异构体可能导致更高的基因翻译效率。通过干扰 TNRC6A 的表达并分析 AGO2-PAR-CLIP 数据，我们揭示了 APA 对翻译效率的影响主要受 miRNAs 调控，并且这种调控依赖于细胞周期。NIH3T3 和其他细胞系之间的差异是由于 NIH3T3 的接触抑制。因此，APA 和 miRNAs 之间的串扰可能是调节蛋白质翻译效率所必需的。
