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Re-awakening endogenous retroviruses: a new link between inflammation and cancer

When TRIM24 gene is inactivated in liver cells, VL30 ERVs are transcribed under the control of retinoic acid receptors (RAR). VL30 RNAs are reverse transcribed into DNA that accumulates in the cytoplasm. This cytoplasmic DNA is then detected by a complex sensing and degradation machinery triggering the inflammatory state. A similar process can be set off by exogenous viral infection.

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

Herquel B, Ouararhni K, Martianov I, Le Gras S, Ye T, Keime C, Lerouge T, Jost B, Cammas F, Losson R, Davidson I.

Nat Struct Mol Biol Mar 2013

Feb. 4, 2013

Over millions of years, mammals have accumulated a large number of endogenous retroviruses in their genome, as inactive remnants of ancient infections. Researchers at IGBMC have shown how reactivation of endogenous retrovirus mimics viral infection and promotes tumor development. The results are published on February 4th in Nature Structural & Molecular Biology.



Endogenous retroviruses

Retroviruses, a virus family that includes HIV, are able to integrate their genetic material into the genome of infected cells and use its resources to multiply. Such integrations occurred many times in the course of evolution, and as a result, thousands of copies of different retroviruses have accumulated in the human genome. Also called retrotransposons, these ancient endogenous retroviruses (ERVs) are major components of our genome. Fortunately, the cell has established a complex mechanism to keep them in an inactive state.

From retinoic acid to hepatocellular carcinoma

As first observed by Régine Losson’s team at the IGBMC, inactivation of the gene encoding the TRIM24 protein resulted in development of hepatocellular carcinoma (liver cancer) through a process involving the retinoic acid (the biologically active derivative of A vitamin) receptor. Irwin Davidson’s team pursued this study further to better understand the hidden mechanism behind this phenomenon. In a new publication, they show that loss of the TRIM24 protein activates expression of the VL30 family of ERVs in liver hepatocytes, whose expression is under the control of retinoic acid receptors. This activation promotes tumor development in several ways: VL30 RNAs are reverse transcribed into DNA that accumulates in the cell body triggering a precancerous inflammatory state. Furthermore, the expression of VL30 elements deregulates neighboring genes and creates aberrant transcription.

Genetic disorders that "mimic" infections

These results highlight the importance of understanding the proteins and mechansims that normally repress ERVs. Indeed, loss of ERV repression can cause diseases with similar effects to those of exogenous viral infections. For example, Aicardi-Goutières syndrome is an early onset progressive encephalopathy, initially mistaken for intrauterine viral infections. In fact, this disorder results from mutations in the machinery that eliminates reverse transcribed ERV DNA allowing it to accumulate and activate the inflammatory response. In the case of TRIM24 gene inactivation, the high expression of VL30 ERVs overloads this degradation machinery in liver cells. Consequently, ERV DNA accumulates and induces an inflammatory state that mimics that seen following hepatitis virus infection, a major risk factor for subsequent development of liver cancer.

Imprimer Envoyer

Université de Strasbourg

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