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.
Steps to reproduce
A part of the computer codes used in the present study are available on the GitHub repository (https://github.com/TheSatoLab/HERV_Pan-cancer_analysis).