KAP 1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control

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.

Primate-restricted KRAB zinc finger proteins and target retrotransposons control gene expression in human neurons

“…This phenomenon was only partly abrogated by inhibiting the cytoplasmic DNA sensor STING (a.k.a.TMEM173) ( fig. S4D), suggesting that it was not just due to ERV or SVA reverse transcripts but likely to additional TE-derived products as observed in TREX1-or ADAR1-inactivated astrocytes or neuronal progenitor cells, respectively, and upon Rec overexpression or treatment with inhibitors of DNA methyltransferases (23,(27)(28)(29)(30)(31). Reciprocally, levels of several ISG transcripts were decreased in HERVK-CRISPRi iN (Fig.…”

Beneficial bacteria activate type-I interferon production via the cytosolic sensors STING and MAVS

“…Having observed that IFN-I-inducing LAB were internalised by macrophages, we explored whether these cytosolic sensors could account for the observed immune responses. We then used THP-1-IFIT1-GLuc cells deficient for STING (STING KO) or MAVS (MAVS KO) (30). We differentiated these cells into macrophages and challenged them with viable cells of PP and LP before measuring GLuc activity.…”

“…THP-1-IFIT1-GLuc express and secrete Gluc under the control of the promoter of the IRF-3-dependent gene IFIT1 and were a gift from Veit Hornung (29). THP-1-IFIT1 deficient for STING or MAVS, and its corresponding control, were kindly provided by Greg Towers and have been previously described (30). THP-1 monocytes were differentiated into macrophages by seeding 5×10 4 cells per well (or 10 6 for immunoblotting) in 96-well plates containing RPMI supplemented with phorbol 12-myristate 13-acetate (PMA) at 20 ng/mL for 48 h as previoulsy described (31).…”

Dynamic Signatures of the Epigenome: Friend or Foe?

“…In stem cells, the complex may also include DNA methyltransferases (DNMT1/3A/3B) that drive DNA methylation [25,86]. Several high-throughput chromatin immunoprecipitation data identified KAP1 and H3K9me3 deposition at various TE families [95][96][97][98], while KAP1 knockdown was shown to upregulate TE activity in ESCs [95,97,98] and, to a lesser extent, in adult tissues [99,100]. The KRAB-ZNF/KAP1 system seems to serve as the first line of TE control upon chromatin decondensation occurring during early developmental stages, at least for some of the TE subclasses.…”

“…Such a feature allows more extensive plasticity and is particularly useful in tissues that require fast adaptation to external stimuli. Indeed, KRAB-ZNF/KAP1 influence on TE regulatory sequences was shown in the cell types with dynamic expression programs, including stem cells [85], neurons [99], and immune system [100]. It remains to be tested to what extent such epigenetic regulation is required for appropriate determination and maintenance of cellular fate, as well as whether other DNA activities (e.g., generation and maintenance of topologically associated domains) may be affected by KRAB-ZNF-TE regulatory network.…”