Fain Jean S, Wangermez Camille, Loriot Axelle, Denoue Claudia, De Smet Charles
Group of Genetics and Epigenetics, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
Group of Computational Biology and Bioinformatics, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
Epigenomes. 2024 Jun 22;8(3):24. doi: 10.3390/epigenomes8030024.
Human tumors progress in part by accumulating epigenetic alterations, which include gains and losses of DNA methylation in different parts of the cancer cell genome. Recent work has revealed a link between these two opposite alterations by showing that DNA hypomethylation in tumors can induce the expression of transcripts that overlap downstream gene promoters and thereby induce their hypermethylation. Preliminary in silico evidence prompted us to investigate if this mechanism applies to the locus harboring , a gene that plays a central role in miRNA biogenesis and RNA interference. Inspection of public RNA-Seq datasets and RT-qPCR experiments show that an alternative transcript starting 13.4 kb upstream of () is expressed specifically in testicular germ cells, and becomes aberrantly activated in different types of tumors, particularly in tumors of the esophagus, stomach, and lung. This expression pattern classifies into the group of "Cancer-Germline" (CG) genes. Analysis of transcriptomic and methylomic datasets provided evidence that transcriptional activation of depends on DNA demethylation of its promoter region. Western blot experiments revealed that encodes a shortened isoform of AGO1, corresponding to a truncation of 75 aa in the N-terminal domain, and which we therefore referred to as "∆NAGO1". Interestingly, significant correlations between hypomethylation/activation of and hypermethylation/repression of were observed upon examination of tumor cell lines and tissue datasets. Overall, our study reveals the existence of a process of interdependent epigenetic alterations in the locus, which promotes swapping between two AGO1 protein-coding mRNA isoforms in tumors.
人类肿瘤的进展部分是通过积累表观遗传改变实现的，这些改变包括癌细胞基因组不同区域DNA甲基化的增加和减少。最近的研究表明，肿瘤中的DNA低甲基化可诱导与下游基因启动子重叠的转录本表达，从而导致其高甲基化，揭示了这两种相反改变之间的联系。初步的计算机模拟证据促使我们研究这种机制是否适用于包含 的基因座，该基因在miRNA生物合成和RNA干扰中起核心作用。对公共RNA-Seq数据集的检查和RT-qPCR实验表明，一种从 上游13.4 kb处起始的可变转录本在睾丸生殖细胞中特异性表达，并在不同类型的肿瘤中异常激活，尤其是在食管、胃和肺癌中。这种表达模式将 归类为“癌胚”（CG）基因组。对转录组和甲基化组数据集的分析提供了证据，表明 的转录激活依赖于其启动子区域的DNA去甲基化。蛋白质免疫印迹实验表明， 编码AGO1的一种缩短异构体，对应于N端结构域截短75个氨基酸，因此我们将其称为“∆NAGO1”。有趣的是，在检查肿瘤细胞系和组织数据集时，观察到 的低甲基化/激活与 的高甲基化/抑制之间存在显著相关性。总体而言，我们的研究揭示了 基因座中存在相互依赖的表观遗传改变过程，该过程促进了肿瘤中两种AGO1蛋白编码mRNA异构体之间的转换。
