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

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

doi:10.1038/nsmb.2496

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

60 Citations (Scopus)

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.

Original language	English
Pages (from-to)	339-346
Number of pages	8
Journal	Nature Structural and Molecular Biology
Volume	20
Issue number	3
DOIs	https://doi.org/10.1038/nsmb.2496
Publication status	Published - Mar 2013
Externally published	Yes

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title = "Trim24-repressed VL30 retrotransposons regulate gene expression by producing noncoding RNA",

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.",

author = "Benjamin Herquel and Khalid Ouararhni and Igor Martianov and {Le Gras}, St{\'e}phanie and Tao Ye and C{\'e}line Keime and Thierry Lerouge and Bernard Jost and Florence Cammas and R{\'e}gine Losson and Irwin Davidson",

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language = "English",

volume = "20",

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AU - Herquel, Benjamin

AU - Ouararhni, Khalid

AU - Martianov, Igor

AU - Le Gras, Stéphanie

AU - Ye, Tao

AU - Keime, Céline

AU - Lerouge, Thierry

AU - Jost, Bernard

AU - Cammas, Florence

AU - Losson, Régine

AU - Davidson, Irwin

PY - 2013/3

Y1 - 2013/3

N2 - 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.

AB - 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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SN - 1545-9993

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SP - 339

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JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

IS - 3

ER -

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

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