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KAP1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control

Tie, CH; Fernandes, L; Conde, L; Robbez-Masson, L; Sumner, RP; Peacock, T; Rodriguez-Plata, MT; ... Rowe, HM; + view all (2018) KAP1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control. EMBO Reports , Article e45000. 10.15252/embr.201745000. (In press). Green open access

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Abstract

Endogenous retroviruses (ERVs) have accumulated in vertebrate genomes and contribute to the complexity of gene regulation. KAP1 represses ERVs during development by its recruitment to their repetitive sequences through KRAB zinc-finger proteins (KZNFs), but little is known about the regulation of ERVs in adult tissues. We observed that KAP1 repression of HERVK14C was conserved in differentiated human cells and performed KAP1 knockout to obtain an overview of KAP1 function. Our results show that KAP1 represses ERVs (including HERV-T and HERV-S) and ZNF genes, both of which overlap with KAP1 binding sites and H3K9me3 in multiple cell types. Furthermore, this pathway is functionally conserved in adult human peripheral blood mononuclear cells. Cytosine methylation that acts on KAP1 regulated loci is necessary to prevent an interferon response, and KAP1-depletion leads to activation of some interferon-stimulated genes. Finally, loss of KAP1 leads to a decrease in H3K9me3 enrichment at ERVs and ZNF genes and an RNA-sensing response mediated through MAVS signaling. These data indicate that the KAP1-KZNF pathway contributes to genome stability and innate immune control in adult human cells.

Type: Article
Title: KAP1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/embr.201745000
Publisher version: http://dx.doi.org/10.15252/embr.201745000
Language: English
Additional information: © 2018 The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: 5‐azacytidine, KAP1 (KRAB‐associated protein 1), SETDB1, adult human cells, endogenous retroviruses, epigenetic control, innate immune genes, retrotransposons
URI: http://discovery.ucl.ac.uk/id/eprint/10054200
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