DS04 - Vie, santé et bien-être

ß-catenin-mediated epigenetic control of the imprinted DLK1/Dio3 locus in liver – DLK1-EPILIV

Submission summary

Liver is a vital organ, ensuring hundreds of metabolic functions and thus finely specialized for its metabolism, which consequently need from birth to adulthood to acquire its metabolic zonation and gradually enter into quiescence. Nevertheless, in response to liver damages, hepatocytes have the capacities to proliferate to maintain the hepatic mass and function, in cooperation with hepatic stem cells. This adaptative response driven by hepatocytes could favor the development of a chronic disease in case of persistent injuries. Chronic liver diseases emerge these recent years as a major health problem regarding to change in our eating habits, but also to abuse in alcohol consumption and infections by hepatitis viruses. Liver disease initiates with a single steatosis which could deteriorate into steatohepatitis (steatosis with inflammation, fibrosis and necrosis), and, finally, to cirrhosis and cancer. These last years, cumulative evidence showed that various microRNAs (miRNAs) extensively contribute to liver pathogenesis, from liver disease to cancer, and thus should constitute potent biomarkers and therapeutic targets for these pathologies. In particular, a cluster of 54 miRNAs originated from the imprinted DLK1/DIO3 locus appear as an attractive player for liver disease establishment since it is crucial both for stem cell and hepatocyte fate in mouse liver following activation of the WNT/ß-catenin signaling, a master regulator pathway for liver zonation and stem cell maintenance. Using deep-sequencing approaches in our mouse models, we importantly demonstrated that ß-catenin orchestrates a specific transcriptional program, resulting in a metabolic reprogramming and an exit from quiescence of hepatocytes, which could favor the establishment of a cancerous switch – an event observed in a third of hepatocellular carcinoma. In particular, we observed that ß-catenin promptly induced the expression of all the constituents of the locus, either expressed from the maternal or the paternal strand, dependently on methylation process and more importantly through direct binding of ß-catenin on its promoter region. In the next three years, using our mouse models, we will unveil how ß-catenin induces a loss of imprinting in the DLK1/DIO3 locus through epigenetic modifications and/or chromatin remodeling, and which factors are recruited in space and time by ß-catenin to modify the locus expression during liver pathogenesis. We will also address the functional consequences of the silencing of this locus by genome editing on hepatocyte metabolic and proliferative properties in different liver pathological contexts. This project deciphering the crosstalk between ß-catenin and epigenetic events (miRNAs, imprinting and chromatin remodeling) for gene expression should highlight new promising targets for regenerative medicine but also for different diseases associated to WNT/ß-catenin signaling such as metabolic syndromes or cancers.

Project coordination

Angélique GOUGELET (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
INSERM U1016 INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

Help of the ANR 265,399 euros
Beginning and duration of the scientific project: December 2017 - 36 Months

Useful links

Explorez notre base de projets financés

 

 

ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter