Murimi-Worstell Daniel A, Murimi-Worstell Irene B, Roy Farrah M, Burn Aidan, Freeman Michael, Puchalski Ralph B, Coffin John M
Program in Molecular Biology and Microbiology, Graduate School of Biomedical Sciences, Tufts University, 150 Harrison Avenue. (617), Boston, MA, 636-6528, United States of America.
Department of Pharmaceutical Economics and Policy, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, United States of America.
Mob DNA. 2025 Jul 16;16(1):29. doi: 10.1186/s13100-025-00365-w.
Human endogenous retroviruses (HERVs) are remnants of ancient viral infections and comprise 6-8% of the human genome. Their biological functions in cancer remain poorly understood, especially in glioblastoma, the most common and deadly primary brain cancer in adults. Prior studies on HERV expression in glioblastoma have yielded conflicting results. Here, we employed orthogonal computational pipelines to address these limitations.
Locus-specific analysis revealed marked heterogeneity of transcription among HERVs within the same clade. We found that individual HERV proviruses are more than twice as likely to be underexpressed in glioblastoma than overexpressed and that most differentially expressed HERVs are exonized within transcripts. These HERVs are enriched in the 3'-terminal exons of transcripts, associated with alternative polyadenylation and contribute conserved polyadenylation signals. We identified HERV expression patterns associated with glioblastoma subtypes and anatomic features. We also identified three proviruses or proviral fragments of particular interest including one associated with survival and one exonized within a currently unannotated cancer-specific transcript. Among the most recently integrated clade of HERVs, excluding solo-LTRs, only the HML-2 provirus at 1q22 is overexpressed in glioblastoma. We report previously undescribed transcripts incorporating this provirus that may encode several proteins.
This study represents the first systematic exploration of the heterogeneity of HERV expression between anatomic features of any cancer. It shows that exaptation of HERV polyadenylation signals and HERV-associated APA are widespread in the human transcriptome and identifies critical structural information regarding the HML-2 1q22 provirus transcript, which has been the focus of several recent analyses. Our findings underscore the importance of locus-specific and anatomic feature-specific HERV analysis and suggest structural and functional roles for HERVs in glioblastoma-associated transcripts.
人类内源性逆转录病毒（HERV）是古代病毒感染的残余物，占人类基因组的6 - 8%。它们在癌症中的生物学功能仍知之甚少，尤其是在胶质母细胞瘤中，这是成人中最常见且致命的原发性脑癌。先前关于胶质母细胞瘤中HERV表达的研究结果相互矛盾。在此，我们采用正交计算流程来解决这些局限性。
位点特异性分析揭示了同一进化枝内HERV之间转录的显著异质性。我们发现，在胶质母细胞瘤中，单个HERV原病毒表达不足的可能性是表达过度的两倍多，并且大多数差异表达的HERV在转录本中被外显子化。这些HERV在转录本的3'末端外显子中富集，与可变多聚腺苷酸化相关，并贡献保守的多聚腺苷酸化信号。我们确定了与胶质母细胞瘤亚型和解剖特征相关的HERV表达模式。我们还确定了三个特别感兴趣的原病毒或原病毒片段，其中一个与生存相关，另一个在当前未注释的癌症特异性转录本中外显子化。在HERV最近整合的进化枝中，不包括单独的长末端重复序列（solo-LTRs），只有位于1q22的HML-2原病毒在胶质母细胞瘤中过度表达。我们报告了以前未描述的包含该原病毒的转录本，这些转录本可能编码几种蛋白质。
本研究首次系统探索了任何癌症解剖特征之间HERV表达的异质性。研究表明，HERV多聚腺苷酸化信号的功能获得和与HERV相关的可变多聚腺苷酸化在人类转录组中广泛存在，并确定了关于HML-2 1q22原病毒转录本的关键结构信息，这是最近几项分析的重点。我们的研究结果强调了位点特异性和解剖特征特异性HERV分析的重要性，并表明HERV在胶质母细胞瘤相关转录本中具有结构和功能作用。
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