Pan-cancer analysis of human endogenous retroviruses and KRAB zinc-finger proteins

Summary: Gene expression aberration is a hallmark of cancers, but the mechanisms underlying such aberrations remain unclear. Human endogenous retroviruses (HERVs) are genomic repetitive elements that potentially function as enhancers. Since numerous HERVs are epigenetically activated in tumors, their activation could cause global gene expression aberrations in tumors. To understand the roles of HERV-derived enhancers in cancers, we performed a pan-cancer analysis focusing on the enhancer activity of HERVs using The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) datasets. We show that HERV activation in tumors leads to the upregulation of hundreds of transcriptional suppressors, namely Krüppel-associated box domain-containing zinc-finger family proteins (KZFPs). KZFP genes are preferentially encoded nearby the activated HERVs in tumors and transcriptionally regulated by these adjacent HERVs. Increased HERV and KZFP expression in tumors was associated with better disease conditions. Increased KZFP expression in cancer cells altered the expression of genes related to the cell cycle and cell-matrix adhesion and suppressed cellular growth, migration, and invasion abilities. Our data suggest that HERV activation in tumors drives the synchronized elevation of KZFP expression, presumably leading to tumor suppression. The related computer codes are available via the GitHub repository (https://github.com/TheSatoLab/HERV_Pan-cancer_analysis). Reference: Endogenous retroviruses drive KRAB zinc-finger protein family expression for tumor suppression. Jumpei Ito†, Izumi Kimura†, Andrew Soper, Alexandre Coudray, Yoshio Koyanagi, Hirofumi Nakaoka, Ituro Inoue, Priscilla Turelli, Didier Trono, and Kei Sato (2020) Science Advances.摘要： 基因表达异常是癌症的标志性特征之一，但其背后的分子机制尚未完全阐明。人类内源性逆转录病毒（HERVs）是基因组重复序列，可潜在充当增强子。鉴于众多HERVs在肿瘤中发生表观遗传激活，其激活可能引发肿瘤内的全局性基因表达异常。为阐明HERV来源增强子在癌症中的作用，我们利用癌症基因组图谱（The Cancer Genome Atlas, TCGA）与癌症细胞系百科全书（Cancer Cell Line Encyclopedia, CCLE）数据集，开展了针对HERV增强子活性的泛癌分析。本研究证实，肿瘤中的HERV激活可诱导数百个转录抑制因子上调，即含KRAB结构域的锌指蛋白家族（Krüppel-associated box domain-containing zinc-finger family proteins, KZFPs）。KZFP基因在肿瘤中优先定位于激活的HERVs邻近区域，并受这些相邻HERVs的转录调控。肿瘤中HERV与KZFP表达水平升高与更佳的临床预后相关。癌细胞内KZFP表达升高会改变与细胞周期、细胞-基质黏附相关的基因表达，并抑制细胞增殖、迁移与侵袭能力。本研究数据表明，肿瘤内的HERV激活可驱动KZFP表达同步上调，推测这一过程可实现肿瘤抑制。 相关计算机代码可通过GitHub仓库（https://github.com/TheSatoLab/HERV_Pan-cancer_analysis）获取。 参考文献： 《内源性逆转录病毒驱动KRAB锌指蛋白家族表达以实现肿瘤抑制》，Jumpei Ito†、Izumi Kimura†、Andrew Soper、Alexandre Coudray、Yoshio Koyanagi、Hirofumi Nakaoka、Ituro Inoue、Priscilla Turelli、Didier Trono、Kei Sato（2020）《Science Advances》。