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MicroRNA‐337‐3p controls hepatobiliary gene expression and transcriptional dynamics during hepatic cell differentiation
Author(s) -
Demarez Céline,
Gérard Claude,
Cordi Sabine,
Poncy Alexis,
Achouri Younes,
Dauguet Nicolas,
Rosa David A.,
Gunning Patrick T.,
Manfroid Isabelle,
Lemaigre Frédéric P.
Publication year - 2018
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.29475
Subject(s) - cholangiocyte , biology , hepatocyte , microbiology and biotechnology , hepatocyte nuclear factors , hepatocyte nuclear factor 4 , transcription factor , progenitor cell , regulator , microrna , regulation of gene expression , cell fate determination , cellular differentiation , embryonic stem cell , progenitor , gene regulatory network , gene expression , gene , stem cell , genetics , endocrinology , nuclear receptor , in vitro
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 relative levels of hepatocyte and cholangiocyte gene expression are determined during differentiation remains poorly understood. Here, we identify microRNA (miR)‐337‐3p as a 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‐β signaling and exerts a biphasic control on the hepatocyte transcription factor hepatocyte nuclear factor 4α by modulating its activation and repression. With the help of an experimentally validated mathematical model, we show that this biphasic control results from an incoherent feedforward loop between miR‐337‐3p and hepatocyte nuclear factor 4α. Conclusion: Our results identify miR‐337‐3p as a regulator of liver development and highlight how tight quantitative control of hepatic cell differentiation is exerted through specific gene regulatory network motifs. (H epatology 2018;67:313‐327).