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

Christopher Hc Tie,Helen M Rowe,Greg J Towers,Robert Gifford,Rebecca P Sumner,Luisa Robbez‐Masson,Liane Fernandes,Javier Herrero,Greta Mickute,Lucia Conde,Tom Peacock,Maria Teresa Rodriguez‐Plata

doi:10.15252/embr.201745000

Christopher Hc Tie, Helen M Rowe + Show 10 more

Open Access

https://doi.org/10.15252/embr.201745000

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Journal: EMBO Reports	Publication Date: Jul 30, 2018
Citations: 94	License type: CC BY 4.0

Affiliation: University College London, University of Glasgow

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.

Highlights

Retrotransposons occupy at least half of the human genome, and individual loci reflect the genetic conflict experienced by the host throughout evolution [1]
The human retrovirus HERVK14C is repressed by KAP1 in undifferentiated and differentiated cells including adult peripheral blood mononuclear cells (PBMCs)
We found using shRNA-mediated RNAi that KAP1 is necessary to regulate endogenous retroviruses (ERVs) in cell lines and in adult peripheral blood mononuclear cells (PBMCs), and to a lesser extent in CD4+ T cells (Figs 1F and EV1F–H), in which the HERVK14C 50LTR was enriched for cytosine methylation (Fig EV1I)

Summary

Introduction

Retrotransposons occupy at least half of the human genome, and individual loci reflect the genetic conflict experienced by the host throughout evolution [1]. LTR retrotransposons are known as endogenous retroviruses (ERVs) because they are derived from exogenous retroviruses. ERVs constitute around 9% of the human genome [2] with important roles in human health and disease. LTRs of the primate-specific retrovirus, MER41, function as natural poised enhancers for a network of interferon-induced genes [3]. The cooption of ERVs into normal processes such as development and immune defense is the result of co-evolution of ERVs and their regulatory DNA sequences, which are scattered across the genome, with their hosts over millions of years [1]

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