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Trim24-repressed VL30 retrotransposons regulate gene expression by producing noncoding RNA

Nature Structural & Molecular Biology volume 20, pages 339–346 (2013)Cite this article

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Abstract

Trim24 (Tif1α) and Trim33 (Tif1γ) interact to form a co-repressor complex that suppresses murine hepatocellular carcinoma. Here we show that Trim24 and Trim33 cooperatively repress retinoic acid receptor–dependent activity of VL30-class endogenous retroviruses (ERVs) in liver. In Trim24-knockout hepatocytes, VL30 derepression leads to accumulation of reverse-transcribed VL30 cDNA in the cytoplasm that correlates with activation of the viral-defense interferon responses mimicking the preneoplastic inflammatory state seen in human liver following exogenous viral infection. Furthermore, upon derepression, VL30 long terminal repeats (LTRs) act as promoter and enhancer elements deregulating expression of neighboring genes and generating enhancer RNAs that are required for LTR enhancer activity in hepatocytes in vivo. These data reinforce the role of the TRIM family of proteins in retroviral restriction and antiviral defense and provide an example of an ERV-derived oncogenic regulatory network.

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Figure 1: Gene expression following Trim24 and Trim33 inactivation.
Figure 2: VL30 expression is dependent on Trim24 and Rarα.
Figure 3: A VL30 LTR acts as an alternative promoter for Mbd1.
Figure 4: LTR-driven transcription.
Figure 5: A VL30 LTR-derived noncoding transcript at the Lcn13 and Bmyc locus.
Figure 6: A VL30 element regulates activity of a cryptic promoter in the Ccdc11 gene.
Figure 7: Lcn13 and Ccdc11 expression is dependent on VL30 LTR–derived eRNAs.
Figure 8: Model for Trim24 tumor-suppressor function in liver.

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Acknowledgements

We thank the following members of the Institute de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France: P. Koebel for AAV production, M. Cervino for mouse genotyping, Y. Lutz for microscopy, D. Umlauf for gift of digitonin, M. Philipps, and S. Vicaire for high-throughput sequencing. We thank the Penn Vector Core, School of Medicine Gene Therapy Program, University of Pennsylvania for the pAAV2/9 plasmid. This work was supported by institutional grants from the Centre National de la Recherche Scientifique, the Institut National de Sante et de la Recherche Médicale, the Université de Strasbourg, the Association pour la Recherche contre le Cancer, the Ligue Nationale contre le Cancer, and the Institut National du Cancer grant No 2008-037, the EuTRACC program of the European Union and the French Agence National pour la Recherche. I.D. is supported as an 'équipe labellisée' of the Ligue Nationale contre le Cancer. B.H. was supported by a fellowship from the Association pour la Recherche contre le Cancer.

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  1. Benjamin Herquel & Florence Cammas

    Present address: Present addresses: Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany (B.H.), and Institut de Recherche sur le Cancer de Montpellier, Montpellier, France (F.C.).,

  2. Régine Losson: Deceased.

Authors and Affiliations

  1. Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    Benjamin Herquel, Khalid Ouararhni, Igor Martianov, Stéphanie Le Gras, Tao Ye, Céline Keime, Thierry Lerouge, Bernard Jost, Florence Cammas & Irwin Davidson

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Contributions

B.H. performed all the RNA-seq, qPCR and ChIP-seq and generated and maintained the different mouse lines together with K.O.; F.C. and K.O. generated and analyzed the MEFs; I.M. performed the Trim24 ChIPs; S.L.G., T.Y. and C.K. performed the bioinformatics analysis of the ChIP-seq and RNA-seq data; T.L. performed the 5′ RACE; B.J. generated the libraries for the ChIP-seq and RNA-seq; B.H., R.L. and I.D. designed experiments analyzed the data and wrote the paper.

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Correspondence to Irwin Davidson.

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Herquel, B., Ouararhni, K., Martianov, I. et al. Trim24-repressed VL30 retrotransposons regulate gene expression by producing noncoding RNA. Nat Struct Mol Biol 20, 339–346 (2013). https://doi.org/10.1038/nsmb.2496

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