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-b signaling and exerts a biphasic control on the hepatocyte transcription factor hepatocyte nuclear factor 4a 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 4a. 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.
Carpentier Rodolphe, Suñer Regina Español, van Hul Noémi, Kopp Janel L., Beaudry Jean–Bernard, Cordi Sabine, Antoniou Aline, Raynaud Peggy, Lepreux Sébastien, Jacquemin Patrick, Leclercq Isabelle A., Sander Maike, Lemaigre Frédéric P., Embryonic Ductal Plate Cells Give Rise to Cholangiocytes, Periportal Hepatocytes, and Adult Liver Progenitor Cells, 10.1053/j.gastro.2011.06.049
Kyrmizi I., Plasticity and expanding complexity of the hepatic transcription factor network during liver development, 10.1101/gad.390906
Odom Duncan T, Dowell Robin D, Jacobsen Elizabeth S, Nekludova Lena, Rolfe P Alexander, Danford Timothy W, Gifford David K, Fraenkel Ernest, Bell Graeme I, Young Richard A, Core transcriptional regulatory circuitry in human hepatocytes, 10.1038/msb4100059
Beaudry J.-B., Pierreux C. E., Hayhurst G. P., Plumb-Rudewiez N., Weiss M. C., Rousseau G. G., Lemaigre F. P., Threshold Levels of Hepatocyte Nuclear Factor 6 (HNF-6) Acting in Synergy with HNF-4 and PGC-1 Are Required for Time-Specific Gene Expression during Liver Development, 10.1128/mcb.02445-05
Alder Olivia, Cullum Rebecca, Lee Sam, Kan Arohumam C., Wei Wei, Yi Yuyin, Garside Victoria C., Bilenky Misha, Griffith Malachi, Morrissy A. Sorana, Robertson Gordon A., Thiessen Nina, Zhao Yongjun, Chen Qian, Pan Duojia, Jones Steven J.M., Marra Marco A., Hoodless Pamela A., Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation, 10.1016/j.celrep.2014.08.046
Parviz Fereshteh, Matullo Christine, Garrison Wendy D, Savatski Laura, Adamson John W, Ning Gang, Kaestner Klaus H, Rossi Jennifer M, Zaret Kenneth S, Duncan Stephen A, Hepatocyte nuclear factor 4α controls the development of a hepatic epithelium and liver morphogenesis, 10.1038/ng1175
Clotman F., Control of liver cell fate decision by a gradient of TGF signaling modulated by Onecut transcription factors, 10.1101/gad.340305
Zong Y., Panikkar A., Xu J., Antoniou A., Raynaud P., Lemaigre F., Stanger B. Z., Notch signaling controls liver development by regulating biliary differentiation, 10.1242/dev.029140
Hofmann J. J., Zovein A. C., Koh H., Radtke F., Weinmaster G., Iruela-Arispe M. L., Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome, 10.1242/dev.052118
Clotman, Development, 129, 1819 (2002)
Takayama K., Kawabata K., Nagamoto Y., Inamura M., Ohashi K., Okuno H., Yamaguchi T., Tashiro K., Sakurai F., Hayakawa T., Okano T., Furue M. K., Mizuguchi H., CCAAT/enhancer binding protein-mediated regulation of TGF receptor 2 expression determines the hepatoblast fate decision, 10.1242/dev.103168
Antoniou Aline, Raynaud Peggy, Cordi Sabine, Zong Yiwei, Tronche François, Stanger Ben Z., Jacquemin Patrick, Pierreux Christophe E., Clotman Frederic, Lemaigre Frederic P., Intrahepatic Bile Ducts Develop According to a New Mode of Tubulogenesis Regulated by the Transcription Factor SOX9, 10.1053/j.gastro.2009.02.051
Poncy Alexis, Antoniou Aline, Cordi Sabine, Pierreux Christophe E., Jacquemin Patrick, Lemaigre Frédéric P., Transcription factors SOX4 and SOX9 cooperatively control development of bile ducts, 10.1016/j.ydbio.2015.05.012
Vanderpool Charles, Sparks Erin E., Huppert Kari A., Gannon Maureen, Means Anna L., Huppert Stacey S., Genetic interactions between hepatocyte nuclear factor-6 and notch signaling regulate mouse intrahepatic bile duct developmentin vivo, 10.1002/hep.24631
Lüdtke Timo H.-W., Christoffels Vincent M., Petry Marianne, Kispert Andreas, Tbx3 promotes liver bud expansion during mouse development by suppression of cholangiocyte differentiation, 10.1002/hep.22700
Shiojiri Nobuyoshi, Takeshita Kentaro, Yamasaki Harufumi, Iwata Takeyuki, Suppression of C/EBP α expression in biliary cell differentiation from hepatoblasts during mouse liver development, 10.1016/j.jhep.2004.07.011
Yamasaki H., Sada A., Iwata T., Niwa T., Tomizawa M., Xanthopoulos K. G., Koike T., Shiojiri N., Suppression of C/EBP expression in periportal hepatoblasts may stimulate biliary cell differentiation through increased Hnf6 and Hnf1b expression, 10.1242/dev.02591
Strick-Marchand H, Inducible differentiation and morphogenesis of bipotential liver cell lines from wild-type mouse embryos, 10.1053/jhep.2002.36123
Arts Florence A., Velghe Amélie I., Stevens Monique, Renauld Jean-Christophe, Essaghir Ahmed, Demoulin Jean-Baptiste, Idiopathic basal ganglia calcification-associatedPDGFRBmutations impair the receptor signalling, 10.1111/jcmm.12443
Chiang H. R., Schoenfeld L. W., Ruby J. G., Auyeung V. C., Spies N., Baek D., Johnston W. K., Russ C., Luo S., Babiarz J. E., Blelloch R., Schroth G. P., Nusbaum C., Bartel D. P., Mammalian microRNAs: experimental evaluation of novel and previously annotated genes, 10.1101/gad.1884710
Subramanian A., Tamayo P., Mootha V. K., Mukherjee S., Ebert B. L., Gillette M. A., Paulovich A., Pomeroy S. L., Golub T. R., Lander E. S., Mesirov J. P., Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles, 10.1073/pnas.0506580102
Tanimizu N., Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors, 10.1242/jcs.01169
Mestdagh Pieter, Lefever Steve, Pattyn Filip, Ridzon Dana, Fredlund Erik, Fieuw Annelies, Ongenaert Maté, Vermeulen Joëlle, De Paepe Anne, Wong Linda, Speleman Frank, Chen Caifu, Vandesompele Jo, The microRNA body map: dissecting microRNA function through integrative genomics, 10.1093/nar/gkr646
Mangan S., Alon U., Structure and function of the feed-forward loop network motif, 10.1073/pnas.2133841100
Kim Dongsan, Kwon Yung-Keun, Cho Kwang-Hyun, The biphasic behavior of incoherent feed-forward loops in biomolecular regulatory networks, 10.1002/bies.20839
Hatzis P., Kyrmizi I., Talianidis I., Mitogen-Activated Protein Kinase-Mediated Disruption of Enhancer-Promoter Communication Inhibits Hepatocyte Nuclear Factor 4 Expression, 10.1128/mcb.00297-06
Du Liqin, Subauste Maria C., DeSevo Christopher, Zhao Zhenze, Baker Michael, Borkowski Robert, Schageman Jeoffrey J., Greer Rachel, Yang Chin-Rang, Suraokar Milind, Wistuba Ignacio I., Gazdar Adi F., Minna John D., Pertsemlidis Alexander, miR-337-3p and Its Targets STAT3 and RAP1A Modulate Taxane Sensitivity in Non-Small Cell Lung Cancers, 10.1371/journal.pone.0039167
Hatziapostolou Maria, Polytarchou Christos, Aggelidou Eleni, Drakaki Alexandra, Poultsides George A., Jaeger Savina A., Ogata Hisanobu, Karin Michael, Struhl Kevin, Hadzopoulou-Cladaras Margarita, Iliopoulos Dimitrios, An HNF4α-miRNA Inflammatory Feedback Circuit Regulates Hepatocellular Oncogenesis, 10.1016/j.cell.2011.10.043
Tanimizu N., Isolation of hepatoblasts based on the expression of Dlk/Pref-1, 10.1242/jcs.00388
Takashima Yasuo, Terada Maiko, Udono Miyako, Miura Shizuka, Yamamoto Junpei, Suzuki Atsushi, Suppression of lethal-7b and miR-125a/b Maturation by Lin28b Enables Maintenance of Stem Cell Properties in Hepatoblasts : Liver Injury/Regeneration, 10.1002/hep.28548
Wei Wei, Hou Juan, Alder Olivia, Ye Xin, Lee Sam, Cullum Rebecca, Chu Andy, Zhao Yongjun, Warner Stephanie M., Knight Darryl A., Yang Decheng, Jones Steven J.M., Marra Marco A., Hoodless Pamela A., Genome-wide microRNA and messenger RNA profiling in rodent liver development implicates mir302b and mir20a in repressing transforming growth factor-beta signaling, 10.1002/hep.26252
Gailhouste Luc, Gomez-Santos Laura, Hagiwara Keitaro, Hatada Izuho, Kitagawa Noriyuki, Kawaharada Kazushi, Thirion Muriel, Kosaka Nobuyoshi, Takahashi Ryou-u, Shibata Tatsuhiro, Miyajima Atsushi, Ochiya Takahiro, miR-148a plays a pivotal role in the liver by promoting the hepatospecific phenotype and suppressing the invasiveness of transformed cells, 10.1002/hep.26422
Laudadio Ilaria, Manfroid Isabelle, Achouri Younes, Schmidt Dominic, Wilson Michael D., Cordi Sabine, Thorrez Lieven, Knoops Laurent, Jacquemin Patrick, Schuit Frans, Pierreux Christophe E., Odom Duncan T., Peers Bernard, Lemaigre Frédéric P., A Feedback Loop Between the Liver-Enriched Transcription Factor Network and Mir-122 Controls Hepatocyte Differentiation, 10.1053/j.gastro.2011.09.001
Rogler Charles E., LeVoci Lauretta, Ader Tammy, Massimi Aldo, Tchaikovskaya Tatyana, Norel Raquel, Rogler Leslie E., MicroRNA-23b cluster microRNAs regulate transforming growth factor-beta/bone morphogenetic protein signaling and liver stem cell differentiation by targeting Smads, 10.1002/hep.22982
Hand Nicholas J., Master Zankhana R., Eauclaire Steven F., Weinblatt Daniel E., Matthews Randolph P., Friedman Joshua R., The microRNA-30 Family Is Required for Vertebrate Hepatobiliary Development, 10.1053/j.gastro.2008.12.006
Tsang John, Zhu Jun, van Oudenaarden Alexander, MicroRNA-Mediated Feedback and Feedforward Loops Are Recurrent Network Motifs in Mammals, 10.1016/j.molcel.2007.05.018
Osella Matteo, Bosia Carla, Corá Davide, Caselle Michele, The Role of Incoherent MicroRNA-Mediated Feedforward Loops in Noise Buffering, 10.1371/journal.pcbi.1001101
AHDJOUDJ S, KAABECHE K, HOLY X, FROMIGUE O, MODROWSKI D, ZERATH E, MARIE P, Transforming growth factor-? inhibits CCAAT/enhancer-binding protein expression and PPAR? activity in unloaded bone marrow stromal cells, 10.1016/j.yexcr.2004.09.013
De Obaldia Maria Elena, Bell J Jeremiah, Wang Xinxin, Harly Christelle, Yashiro-Ohtani Yumi, DeLong Jonathan H, Zlotoff Daniel A, Sultana Dil Afroz, Pear Warren S, Bhandoola Avinash, T cell development requires constraint of the myeloid regulator C/EBP-α by the Notch target and transcriptional repressor Hes1, 10.1038/ni.2760
Bibliographic reference
Demarez, Céline ; Gérard, Claude ; Cordi, Sabine ; Poncy, Alexis ; Achouri, Younes ; et. al. MicroRNA-337-3p controls hepatobiliary gene expression and transcriptional dynamics during hepatic cell differentiation. In: Hepatology, Vol. 67, p. 313-327 (2018)
