KAP1 regulates ERVs in differentiated human cells and contributes to innate immune control

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 differentiated cells. 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 ZNFs, both of which overlap with KAP1 binding sites and H3K9me3 in multiple cell types. Furthermore, this pathway is functionally conserved in primary 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 ZNFs 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 differentiated human cells. Overall design: Dissection of which transposons and genes KAP1 regulates in differentiated human cells

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Tie CH, Fernandes L, Conde L, Robbez-Masson L, Sumner RP, Peacock T, Rodriguez-Plata MT, Mickute G, Gifford R, Towers GJ, Herrero J, Rowe HM