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

Autor: Tie CH; Division of Infection and Immunity, University College London, London, UK., Fernandes L; Division of Infection and Immunity, University College London, London, UK., Conde L; Bill Lyons Informatics Centre, UCL Cancer Institute, London, UK., Robbez-Masson L; Division of Infection and Immunity, University College London, London, UK., Sumner RP; Division of Infection and Immunity, University College London, London, UK., Peacock T; Division of Infection and Immunity, University College London, London, UK., Rodriguez-Plata MT; Division of Infection and Immunity, University College London, London, UK., Mickute G; Division of Infection and Immunity, University College London, London, UK., Gifford R; MRC-University of Glasgow Centre for Virus Research, Glasgow, UK., Towers GJ; Division of Infection and Immunity, University College London, London, UK., Herrero J; Bill Lyons Informatics Centre, UCL Cancer Institute, London, UK., Rowe HM; Division of Infection and Immunity, University College London, London, UK h.rowe@ucl.ac.uk.
Jazyk: angličtina
Zdroj: EMBO reports [EMBO Rep] 2018 Oct; Vol. 19 (10). Date of Electronic Publication: 2018 Jul 30.
DOI: 10.15252/embr.201745000
Abstrakt: 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.
(© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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