Université Clermont Auvergne, CNRS, Inserm, iGReD, Clermont-Ferrand F-63000, France.
Biostatistics Department, Délégation à la Recherche Clinique et à l'Innovation, Clermont-Ferrand Hospital, Clermont-Ferrand 63003, France.
Hum Mol Genet. 2022 Aug 17;31(15):2606-2622. doi: 10.1093/hmg/ddac056.
Besides the consequences of retrotransposition, long interspersed element 1 (L1) retrotransposons can affect the host genome through their antisense promoter. In addition to the sense promoter, the evolutionarily recent L1 retrotransposons, which are present in several thousand copies, also possess an anti-sense promoter that can produce L1 chimeric transcripts (LCT) composed of the L1 5' UTR followed by the adjacent genomic sequence. The full extent to which LCT expression occurs in a given tissue and whether disruption of the defense mechanisms that normally control L1 retrotransposons affects their expression and function in cancer cells, remain to be established. By using CLIFinder, a dedicated bioinformatics tool, we found that LCT expression was widespread in normal brain and aggressive glioma samples, and that approximately 17% of recent L1 retrotransposons, from the L1PA1 to L1PA7 subfamilies, were involved in their production. Importantly, the transcriptional activities of the L1 antisense promoters and of their host loci were coupled. Accordingly, we detected LCT-producing L1 retrotransposons mainly in transcriptionally active genes and genomic loci. Moreover, changes in the host genomic locus expression level in glioma were associated with a similar change in LCT expression level, regardless of the L1 promoter methylation status. Our findings support a model in which the host genomic locus transcriptional activity is the main driving force of LCT expression. We hypothesize that this model is more applicable when host gene and LCT are transcribed from the same strand.
除了反转录的后果，长散布元件 1（L1）反转录转座子可以通过其反义启动子影响宿主基因组。除了有意义的启动子外，进化上较新的 L1 反转录转座子，存在于几千个拷贝中，也具有反义启动子，可以产生由 L1 5'UTR 跟随相邻基因组序列组成的 L1 嵌合转录本（LCT）。在特定组织中 LCT 表达的程度以及破坏通常控制 L1 反转录转座子的防御机制是否会影响它们在癌细胞中的表达和功能，仍有待确定。通过使用专用的生物信息学工具 CLIFinder，我们发现 LCT 在正常大脑和侵袭性神经胶质瘤样本中广泛表达，并且大约 17%的最近的 L1 反转录转座子，来自 L1PA1 到 L1PA7 亚家族，参与其产生。重要的是，L1 反义启动子和它们的宿主基因座的转录活性是耦合的。因此，我们检测到主要在转录活跃基因和基因组基因座中产生 LCT 的 L1 反转录转座子。此外，在神经胶质瘤中宿主基因组基因座表达水平的变化与 LCT 表达水平的相似变化相关，而与 L1 启动子甲基化状态无关。我们的研究结果支持这样一种模型，即宿主基因组基因座的转录活性是 LCT 表达的主要驱动力。我们假设，当宿主基因和 LCT 从同一链转录时，这种模型更适用。
