棉尾兔乳头状瘤病毒在肿瘤组织中的完整转录图。

IF 5.5 1区 医学 Q1 MICROBIOLOGY PLoS Pathogens Pub Date : 2024-10-25 eCollection Date: 2024-10-01 DOI:10.1371/journal.ppat.1012649
Pengfei Jiang, Vladimir Majerciak, Jiafen Hu, Karla Balogh, Thomas J Meyer, Maggie Cam, Debra Shearer, Matthew Lanza, Neil D Christensen, Zhi-Ming Zheng
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引用次数: 0

摘要

棉尾兔乳头状瘤病毒(CRPV)是第一种与肿瘤发生有关的乳头状瘤病毒,90多年来一直被用作研究乳头状瘤病毒发病机制的有力模型。然而,缺乏对 CRPV 转录组的全面分析阻碍了人们对 CRPV 生物学和分子发病机制的了解。在这里,我们报告了从赫氏 CRPV 诱导的皮肤肿瘤组织中构建的完整 CRPV 转录图谱。通过使用 RNA-seq 结合长线程 PacBio Iso-seq、5'和 3' RACE、引物漫游 RT-PCR、Northern 印迹和 RNA 原位杂交,我们证明了 CRPV 基因组至少从五个不同的主要启动子(P)单向转录其早期和晚期 RNA 转录本,并在两个主要的多腺苷酸化(pA)位点对其转录本进行多腺苷酸化。病毒早期转录本主要由三个 "早期 "启动子(P90、P156 和 P907)转录,并在 nt 4368 处通过 nt 4351 处的早期多腺苷化信号(PAS)进行多腺苷化。与其他低风险人类乳头瘤病毒和动物乳头瘤病毒一样,CRPV E6 和 E7 转录本也是由三个独立的早期启动子转录的。来自两个 "晚期 "启动子(P7525 和 P1225)的转录本利用 E1^E4 的早期 PAS 或位于第 7415 nt 处 L2 和 L1 RNA 多聚腺苷酸化的第 7399 位晚期 PAS 分别表达囊膜 L2 和 L1 蛋白。通过使用绘制的四个 5'剪接位点和三个 3'剪接位点,CRPV RNA 转录本经过广泛的替代剪接,产生了 33 种以上的病毒 RNA 异构体,用于生产至少 12 种病毒蛋白,其中一些无需密码子优化即可在兔 RK13 和人 HEK293T 细胞中表达。本研究首次构建的完整 CRPV 转录图谱将加深我们对 CRPV 基因的结构和表达及其对分子致病和肿瘤发生的贡献的了解。
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The full transcription map of cottontail rabbit papillomavirus in tumor tissues.

Cottontail rabbit papillomavirus (CRPV), the first papillomavirus associated with tumor development, has been used as a powerful model to study papillomavirus pathogenesis for more than 90 years. However, lack of a comprehensive analysis of the CRPV transcriptome has impeded the understanding of CRPV biology and molecular pathogenesis. Here, we report the construction of a complete CRPV transcription map from Hershey CRPV-induced skin tumor tissues. By using RNA-seq in combination with long-reads PacBio Iso-seq, 5' and 3' RACE, primer-walking RT-PCR, Northern blot, and RNA in situ hybridization, we demonstrated that the CRPV genome transcribes its early and late RNA transcripts unidirectionally from at least five distinct major promoters (P) and polyadenylates its transcripts at two major polyadenylation (pA) sites. The viral early transcripts are primarily transcribed from three "early" promoters, P90, P156, and P907 and polyadenylated at nt 4368 by using an early polyadenylation signal (PAS) at nt 4351. Like other low-risk human papillomaviruses and animal papillomaviruses, CRPV E6 and E7 transcripts are transcribed from three separate early promoters. Transcripts from two "late" promoters, P7525, and P1225, utilize either an early PAS for E1^E4 or a late PAS at 7399 for L2 and L1 RNA polyadenylation at nt 7415 to express capsid L2 and L1 proteins respectively. By using the mapped four 5' splice sites and three 3' splice sites, CRPV RNA transcripts undergo extensive alternative splicing to produce more than 33 viral RNA isoforms for production of at least 12 viral proteins, some of which without codon optimization are expressible in rabbit RK13 and human HEK293T cells. The constructed full CRPV transcription map in this study for the first time will enhance our understanding of the structures and expressions of CRPV genes and their contribution to molecular pathogenesis and tumorigenesis.

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PLoS Pathogens
PLoS Pathogens MICROBIOLOGY-PARASITOLOGY
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期刊介绍: Bacteria, fungi, parasites, prions and viruses cause a plethora of diseases that have important medical, agricultural, and economic consequences. Moreover, the study of microbes continues to provide novel insights into such fundamental processes as the molecular basis of cellular and organismal function.
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