Plasticity and expanding complexity of the hepatic transcription factor network during liver development.
Cross-regulatory cascades between hepatic transcription factors have been implicated in the determination of the hepatic phenotype. Analysis of recruitments to regulatory regions and the temporal and spatial expression pattern of the main hepatic regulators during liver development revealed a gradual increase in complexity of autoregulatory and cross-regulatory circuits. Within these circuits we identified a core group of six transcription factors, which regulate the expression of each other and the expression of other downstream hepatic regulators. Changes in the promoter occupancy patterns during development included new recruitments, release, and exchange of specific factors. We also identified promoter and developmental stage-specific dual regulatory functions of certain factors as an important feature of the network. Inactivation of HNF-4alpha in embryonic, but not in adult, liver resulted in the diminished expression of most hepatic factors, demonstrating that the stability of the network correlates with its complexity. The results illustrate the remarkable flexibility of a self-sustaining transcription factor network, built up by complex dominant and redundant regulatory motifs in developing hepatocytes.
Kyrmizi
Irene
I
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Hellas, 711 10 Herakleion, Crete, Greece.
Hatzis
Pantelis
P
Katrakili
Nitsa
N
Tronche
Francois
F
Gonzalez
Frank J
FJ
Talianidis
Iannis
I
D000818:Animals; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D005091:Exons; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D008099:Liver / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013047:Specific Pathogen-Free Organisms; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors