Threshold levels of hepatocyte nuclear factor 6 (HNF-6) acting in synergy with HNF-4 and PGC-1alpha are required for time-specific gene expression during liver development.
During liver development, hepatocytes undergo a maturation process that leads to the fully differentiated state. This relies at least in part on the coordinated action of liver-enriched transcription factors (LETFs), but little is known about the dynamics of this coordination. In this context we investigate here the role of the LETF hepatocyte nuclear factor 6 (HNF-6; also called Onecut-1) during hepatocyte differentiation. We show that HNF-6 knockout mouse fetuses have delayed expression of glucose-6-phosphatase (g6pc), which catalyzes the final step of gluconeogenesis and is a late marker of hepatocyte maturation. Using a combination of in vivo and in vitro gain- and loss-of-function approaches, we demonstrate that HNF-6 stimulates endogenous g6pc gene expression directly via a synergistic and interdependent action with HNF-4 and that it involves coordinate recruitment of the coactivator PGC-1alpha. The expression of HNF-6, HNF-4, and PGC-1alpha rises steadily during liver development and precedes that of g6pc. We provide evidence that threshold levels of HNF-6 are required to allow synergism between HNF-6, HNF-4, and PGC-1alpha to induce time-specific expression of g6pc. Our observations on the regulation of g6pc by HNF-6 provide a model whereby synergism, interdependency, and threshold concentrations of LETFs and coactivators determine time-specific expression of genes during liver development.
Beaudry
Jean-Bernard
JB
Box 7529, 75 Avenue Hippocrate, B-1200 Brussels, Belgium.
Pierreux
Christophe E
CE
Hayhurst
Graham P
GP
Plumb-Rudewiez
Nicolas
N
Weiss
Mary C
MC
Rousseau
Guy G
GG
Lemaigre
Frédéric P
FP
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D005952:Glucose-6-Phosphatase / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D051559:Hepatocyte Nuclear Factor 6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology; D006801:Humans; D008099:Liver / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
D051557:Hepatocyte Nuclear Factor 4; D051559:Hepatocyte Nuclear Factor 6; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D005952:Glucose-6-Phosphatase