MiR-337-3p controls hepatobiliary gene expression and transcriptional dynamics during hepatic cell differentiation.

[en] Transcriptional networks control the differentiation of the hepatocyte and cholangiocyte lineages from embryonic liver progenitor cells, and their subsequent maturation to the adult phenotype. However, how accurate levels of hepatocyte and cholangiocyte gene expression are determined during differentiation remains poorly understood. Here we identify miR-337-3p as a novel regulator of liver development. MiR-337-3p stimulates expression of cholangiocyte genes and represses hepatocyte genes in undifferentiated progenitor cells in vitro and in embryonic mouse livers. Beyond the stage of lineage segregation, miR-337-3p controls the transcriptional network dynamics of developing hepatocytes, and balances both cholangiocyte populations that constitute the ductal plate. MiR-337-3p requires Notch and Transforming Growth Factor-beta signaling, and exerts a biphasic control on the hepatocyte transcription factor Hepatocyte Nuclear Factor (HNF) 4alpha, by modulating its activation and repression. With help of an experimentally validated mathematical model we show that this biphasic control results from an incoherent feedforward loop between miR-337-3p and HNF4alpha. CONCLUSION: Our results identify miR-337-3p as a novel regulator of liver development, and highlight how tight quantitative control of hepatic cell differentiation is exerted via specific gene regulatory network motifs. This article is protected by copyright. All rights reserved.

Disciplines :

Anatomy (cytology, histology, embryology...) & physiology

Author, co-author :

Demarez, Celine

Gerard, Claude

Cordi, Sabine

Poncy, Alexis

Achouri, Younes

Dauguet, Nicolas

Rosa, David A.

Gunning, Patrick T.

Manfroid, Isabelle ; Université de Liège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire

Lemaigre, Frederic P.

Language :

English

Title :

MiR-337-3p controls hepatobiliary gene expression and transcriptional dynamics during hepatic cell differentiation.

Publication date :

2018

Journal title :

Hepatology

ISSN :

0270-9139

eISSN :

1527-3350

Publisher :

John Wiley & Sons, Hoboken, United States - New Jersey

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 23 January 2018

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