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Regulatory networks of liver enriched transcription factors in liver biology and disease

: Borlak, J.; Klempnauer, J.; Schrem, H.


Borlak, J.:
Handbook of toxicogenomics : Strategies and applications
Weinheim: Wiley-VCH, 2005
ISBN: 3-527-30342-1
Aufsatz in Buch
Fraunhofer ITEM ()
Genetic toxicology; Genetics; Proteomics; Gene expression

New genomic platform technologies enable the study of complex genomes and proteomes for improved target identification and validation. This leads to high-density datasets, on the order of millions of data points per day. Turning data into knowledge will be one of the biggest challenges of the 21st century. Here we describe concisely
the role of liver-enriched transcription factors in regulatory gene networks and focus on liver development function and disease. This knowledge will prove to be indispensable for interpretation of high-density genomic datasets that are being produced in pharmaco- and toxicogenomics.
Numerous studies have established the pivotal role of liver-enriched transcription factors in organ development and cellular function, and there is conclusive evidence for transcription factors acting in concert in liver-specific gene expression. During organ development and in progenitor cells the timely expression of certain transcription
factors is necessary for cellular differentiation, and there is overwhelming evidence for hierarchical and cooperative principles in a networked environment of transcription factors. The search for molecular switches that control stem-cell imprinting and liver-specific functions has led to the discovery of many interactions between such different molecules as transcription factors, coactivators, corepressors, enzymes, DNA, and RNA. Many of these interactions either repress or activate liverspecific gene expression. Six families of liver-enriched transcription factors have been characterized so far: HNF-1, HNF-3, HNF-4, HNF-6, C/EBP, and D-binding protein (DBP). The analysis of the tissue distribution of these factors and the determination of their hierarchical relations have led to the hypothesis that cooperation of liver-enriched transcription factors with the ubiquitous trans-activating factors is necessary, and possibly even sufficient, for the maintenance of liver-specific gene transcription. HNFs (hepatocyte nuclear factors) are a heterogeneous class of evolutionarily conserved transcription factors that contain several families of liver-enriched transcription factors (HNF-1, HNF-3, HNF-4, and HNF-6) that are required for hepatocellular differentiation as well as in hepatic carbohydrate, lipid, and protein metabolism (Schrem et al., 2002). Major regulatory functions in the liver, including cell cycle control, carcinogenesis, circadian gene regulation, liver regeneration, and apoptosis, are controlled by C/EBPs (CAAT/enhancer binding proteins) (see also Figure 14.2) and DBP (Schrem et al., 2004). In this chapter we highlight striking examples of relevant network interactions of liver-enriched transcription factors with a significant impact on liver biology to further an understanding of the molecular events linked to liver disease and drug-induced toxicity.