Identification of novel wraparound transcripts in JC polyomavirus
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JC polyomavirus (JCPyV) is a ubiquitous pathogen causing progressive multifocal leukoencephalopathy (PML) in immunocompromised individuals. Polyomaviruses (PyVs) utilize complex transcriptional regulation mechanisms to express diverse mRNAs from their compact, double-stranded circular DNA genomes. A recent study employed next-generation sequencing (NGS) to provide a detailed transcriptome atlas of PyVs, including BK polyomavirus and simian virus 40. However, detailed information regarding the JCPyV transcriptome remains limited. Here, we conducted a comprehensive analysis combining short-read and long-read NGS methods to unveil the detailed transcriptome atlas of JCPyV. RNA isolated from IMR-32 and 293 cells transfected with the circular JCPyV genome was analyzed by NGS, leading to the discovery of 39 novel viral transcripts in addition to 12 previously annotated ones. Among these novel transcripts, we identified characteristic wraparound transcripts, conserved across PyVs, which are constructed from long primary transcripts generated through continuous, multiple rounds of circular transcription of the viral genome. These wraparound transcripts included both late transcripts harboring leader-to-leader repeated sequences and SuperT transcripts containing multiple LxCxE motifs. Notably, wraparound transcripts, including a SuperT transcript, were also detected in brain tissues from PML patients. Collectively, this study significantly expands our understanding of the JCPyV transcriptome, revealing the expression of wraparound transcripts in PML lesions. These findings provide valuable insights into the molecular basis of JCPyV gene expression and PML pathogenesis, potentially facilitating the development of effective countermeasures against PML.
Author Summary
JC polyomavirus (JCPyV) was first identified in 1971 from the brain tissue of a patient with progressive multifocal leukoencephalopathy (PML), a life-threatening neurological disease. Despite over 50 years since the pathogen’s identification, the prognosis for PML remains extremely poor due to the lack of effective therapeutics. Elucidating the JCPyV transcriptome can expand our understanding of viral gene expression and PML pathogenesis, potentially providing targets for novel therapeutic strategies. Here, we employed a combination of three next-generation sequencing technologies to explore novel viral transcripts, creating a detailed transcriptome atlas of JCPyV. We identified 39 novel viral transcripts in addition to the 12 previously annotated ones in cultured cells transfected with the JCPyV genome. These novel transcripts included wraparound transcripts, which arise from continuous, multiple rounds of circular transcription of the viral genome. Wraparound transcripts were characterized by the presence of tandem repeats of approximately 100 nucleotides. Notably, these characteristic wraparound transcripts were also detected in brain tissues from PML patients. Our study provides new insights into JCPyV gene expression, potentially contributing to the development of effective therapeutics.
