Lari Azra, Shah Sahil B, Mao Xiaowen, Sanghrajka Priyanka, Karijolich John, Lareau Liana F, Glaunsinger Britt A
bioRxiv. 2025 May 15:2025.05.14.654096. doi: 10.1101/2025.05.14.654096.
The accumulation of RNA Polymerase III (Pol III) transcribed short interspersed nuclear element (SINE) retrotransposon RNA is a hallmark of various cellular stressors, including DNA virus infection. However, the molecular mechanisms driving the induction of these normally repressed loci are largely undefined. Here, we reveal that in addition to Pol III transcriptional induction, gammaherpesvirus infection stimulates mRNA-like 3' end processing of SINE RNAs that leads to their stabilization. We developed a convolutional neural network (CNN)-based model that identified a polyadenylation-associated motif as the key hallmark of infection-induced SINEs. Indeed, mRNA polyadenylation machinery is recruited in a Pol III-dependent manner to virus-induced loci, including B2 SINE and tRNA genes. Infection causes enhanced polyadenylation of SINE ncRNA, which is required for its stable accumulation. This virus-host interaction therefore highlights an inducible, coupled relationship between Pol III transcription and mRNA-like polyadenylation. It also reveals that co-option of the polyadenylation machinery by Pol III is a mechanism to increase the abundance of noncoding RNA during pathogenic stress.
Short interspersed nuclear elements (SINEs) are hyperabundant and transcribed by RNA polymerase III (Pol III) to produce noncoding retrotransposons. Although generally not detectable in healthy somatic cells, SINE RNA expression is upregulated during stress, including viral infection and inflammatory diseases. We used gammaherpesvirus infection to uncover pathways leading to increased SINE RNA expression. Using a newly developed deep learning model and genomics analyses, we reveal that infection-induced accumulation of SINEs is driven by increased Pol III transcription and Pol III-dependent recruitment of polyadenylation machinery. This stimulates polyadenylation of SINEs, which is a known stabilizer of these noncoding transcripts. Our findings suggest that inducible alterations to Pol III transcript 3' end processing modulate the abundance of noncoding retrotransposons during pathogenic stress.
RNA聚合酶III（Pol III）转录的短散在核元件（SINE）逆转录转座子RNA的积累是包括DNA病毒感染在内的各种细胞应激源的一个标志。然而，驱动这些通常被抑制的基因座诱导的分子机制在很大程度上尚不清楚。在这里，我们揭示，除了Pol III转录诱导外，γ疱疹病毒感染还刺激SINE RNA的mRNA样3'末端加工，从而导致其稳定。我们开发了一种基于卷积神经网络（CNN）的模型，该模型将多聚腺苷酸化相关基序识别为感染诱导的SINE的关键标志。事实上，mRNA多聚腺苷酸化机制以Pol III依赖的方式被招募到病毒诱导的基因座，包括B2 SINE和tRNA基因。感染导致SINE非编码RNA的多聚腺苷酸化增强，这是其稳定积累所必需的。因此，这种病毒-宿主相互作用突出了Pol III转录与mRNA样多聚腺苷酸化之间的一种可诱导的耦合关系。它还揭示了Pol III对多聚腺苷酸化机制的利用是在致病应激期间增加非编码RNA丰度的一种机制。
短散在核元件（SINE）数量过多，由RNA聚合酶III（Pol III）转录以产生非编码逆转录转座子。虽然在健康体细胞中通常检测不到，但SINE RNA表达在应激期间会上调，包括病毒感染和炎症性疾病。我们利用γ疱疹病毒感染来揭示导致SINE RNA表达增加的途径。通过使用新开发的深度学习模型和基因组学分析，我们揭示感染诱导的SINE积累是由Pol III转录增加和多聚腺苷酸化机制的Pol III依赖招募驱动的。这刺激了SINE的多聚腺苷酸化，而多聚腺苷酸化是这些非编码转录本的已知稳定剂。我们的研究结果表明，在致病应激期间，对Pol III转录本3'末端加工的可诱导改变调节了非编码逆转录转座子的丰度。
