Plasticity and expanding complexity of the hepatic transcription factor network during liver development
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-4α 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.
- National Cancer Institute United States
- National Institutes of Health United States
- Foundation for Research and Technology Hellas Greece
- French National Centre for Scientific Research France
- Collège de France France
Male, Chromatin Immunoprecipitation, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Regulation, Developmental, Cell Differentiation, Exons, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Specific Pathogen-Free Organisms, Mice, Hepatocyte Nuclear Factor 4, Liver, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Hepatocytes, Animals, Female, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], RNA, Messenger, Promoter Regions, Genetic, Transcription Factors
Male, Chromatin Immunoprecipitation, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Regulation, Developmental, Cell Differentiation, Exons, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Specific Pathogen-Free Organisms, Mice, Hepatocyte Nuclear Factor 4, Liver, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Hepatocytes, Animals, Female, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], RNA, Messenger, Promoter Regions, Genetic, Transcription Factors
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