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MiR-337-3p controls hepatobiliary gene expression and transcriptional dynamics during hepatic cell differentiation
Hepatology ( IF 13.5 ) Pub Date : 2017-11-16 , DOI: 10.1002/hep.29475
Céline Demarez 1 , Claude Gérard 1 , Sabine Cordi 1 , Alexis Poncy 1 , Younes Achouri 1, 2 , Nicolas Dauguet 1 , David A. Rosa 3 , Patrick T. Gunning 3 , Isabelle Manfroid 4 , Frédéric P. Lemaigre 1
Affiliation  

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. (Hepatology 2018;67:313‐327).

中文翻译:

MiR-337-3p 控制肝细胞分化过程中的肝胆基因表达和转录动力学

转录网络控制肝细胞和胆管细胞谱系从胚胎肝祖细胞的分化以及它们随后成熟为成体表型。然而,肝细胞和胆管细胞基因表达的相对水平如何在分化过程中被确定仍然知之甚少。在这里,我们确定 microRNA (miR)-337-3p 作为肝脏发育的调节剂。miR-337-3p 在体外和胚胎小鼠肝脏中刺激胆管细胞基因的表达并抑制未分化祖细胞中的肝细胞基因。在谱系分离阶段之外,miR-337-3p 控制发育中肝细胞的转录网络动态并平衡构成导管板的两个胆管细胞群。miR-337-3p 需要 Notch 和转化生长因子-β 信号传导,并通过调节其激活和抑制对肝细胞转录因子肝细胞核因子 4α 施加双相控制。在实验验证的数学模型的帮助下,我们表明这种双相控制源于 miR-337-3p 和肝细胞核因子 4α 之间的不连贯前馈回路。结论:我们的结果确定 miR-337-3p 是肝脏发育的调节剂,并强调了通过特定基因调控网络基序对肝细胞分化进行严格的定量控制。(肝病学 2018 年;67:313-327)。我们表明这种双相控制是由 miR-337-3p 和肝细胞核因子 4α 之间的不连贯前馈回路引起的。结论:我们的结果将 miR-337-3p 鉴定为肝脏发育的调节剂,并强调了通过特定基因调控网络基序对肝细胞分化进行严格的定量控制。(肝病学 2018 年;67:313-327)。我们表明这种双相控制是由 miR-337-3p 和肝细胞核因子 4α 之间的不连贯前馈回路引起的。结论:我们的结果确定 miR-337-3p 是肝脏发育的调节剂,并强调了通过特定基因调控网络基序对肝细胞分化进行严格的定量控制。(肝病学 2018 年;67:313-327)。
更新日期:2017-11-16
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