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Vol. 54, Issue 1, 129-158, March 2002

Liver-Enriched Transcription Factors in Liver Function and Development. Part I: The Hepatocyte Nuclear Factor Network and Liver-Specific Gene Expression

Harald Schrem, Jürgen Klempnauer and Jürgen Borlak

Viszeral und Transplantationschirurgie, Medizinische Hochschule Hannover (H.S., J.K.); and Center of Drug Research and Medical Biotechnology, Fraunhofer Institut für Toxikologie und Aerosolforschung, Hannover, Germany (J.B.)

I. Transcription Factors and Gene Regulation
    A. Principal Mechanisms
    B. Chromatin Higher Order Structure and Transcription Factor Function
        1. ATP-Utilizing Chromatin Remodeling Complexes: Switch/Sucrose Nonfermenting and Relatives.
            a. Switch/Sucrose Nonfermenting Subunits and Their Interaction with DNA.
            b. Switch/Sucrose Nonfermenting Complex and Cell Cycle Control: Impact on Liver Regeneration?
            c. Components of the Switch/Sucrose Nonfermenting Complex as Cofactors for Nuclear Receptors.
            d. Further Multiprotein Complexes with Homology to the Switch/Sucrose Nonfermenting ATPase.
        2. Chromatin Modification: Reversible Acetylation of Histone Lysines.
        3. Chromatin Modification: Reversible Phosphorylation of Histone Serines and Threonines.
        4. Chromatin Modification: Reversible Ubiquitination of Histone Lysines.
        5. Chromatin Modification: Reversible DNA Methylation.
    C. Epigenetics
    D. Position-Effect Variegation
    E. Formation of the Multiprotein Complex
II. Classification of Liver-Enriched Transcription Factors
    A. DNA-Binding Domain of Hepatocyte Nuclear Factor-1
    B. DNA-Binding Domain of Hepatocyte Nuclear Factor-3
    C. DNA-Binding Domain of Hepatocyte Nuclear Factor-4
    D. DNA-Binding Domain of Hepatocyte Nuclear Factor-6
    E. DNA-Binding Domain of CCAAT/Enhancer-Binding Proteins
III. Molecular Regulation of Liver Function
    A. Liver-Specific Gene Expression
    B. Liver-Enriched Transcription Factors
IV. Hepatocyte Nuclear Factors
    A. The Hepatocyte Nuclear Factor-1 Family
        1. Dimerization Cofactor of Hepatocyte Nuclear Factor-1alpha and Liver-Specific Gene Expression.
    B. The Hepatocyte Nuclear Factor-3 Subfamily
    C. The Hepatocyte Nuclear Factor-4 Subfamily
        1. The Structure and Domains of Hepatocyte Nuclear Factor-4.
        2. The Relevance of Hepatocyte Nuclear Factor-4 Splice Variants.
        3. Homo- and Heterodimerization of Hepatocyte Nuclear Factor-4 Proteins.
        4. Regulation of Hepatocyte Nuclear Factor-4 Function by Phosphorylation.
        5. Agonistic and Antagonistic Ligands for the Nuclear Receptor Hepatocyte Nuclear Factor-4alpha .
        6. Acetylation of Nucleosomal Histones and Hepatocyte Nuclear Factor-4 by cAMP Response Element-Binding Protein.
        7. Chicken Ovalbumin Upstream Promoter-Transcription Factors and Hepatocyte Nuclear Factor-4: Cooperation and Competition.
    D. Hepatocyte Nuclear Factor-6
        1. Splice Variants of Hepatocyte Nuclear Factor-6.
        2. Hepatocyte Nuclear Factor-6 in Development.
        3. Regulation of Hepatocyte Nuclear Factor-6 Expression by Growth Hormone.
        4. Inhibitory Protein-Protein Interaction between Hepatocyte Nuclear Factor-6 and a Nuclear Receptor.
    E. Coactivators for Hepatocyte Nuclear Factor-1 and Hepatocyte Nuclear Factor-4
    F. The Hepatocyte Nuclear Factor Network and Tissue-Specific Gene Expression
        1. Hepatocyte Nuclear Factor-1 Regulates Hepatocyte Nuclear Factor-4alpha Expression.
        2. Hepatocyte Nuclear Factor-1alpha and Hepatocyte Nuclear Factor-4 Regulate Hepatocyte Nuclear Factor-1alpha Expression.
        3. Hepatocyte Nuclear Factor-6, OC-2, Hepatocyte Nuclear Factor-3beta , and CCAAT/Enhancer-Binding Proteins Regulate Hepatocyte Nuclear Factor-3beta Expression.
        4. Hepatocyte Nuclear Factor-1alpha Regulates Hepatocyte Nuclear Factor-3gamma in the Liver.
        5. Competition and Cooperation ("Coopetition") between Hepatocyte Nuclear Factor-3alpha and Hepatocyte Nuclear Factor-3beta .
    G. Human Disease Due to Mutations in Hepatocyte Nuclear Factors
    H. Evidence from Knockout Experiments
    I. Lack of Confirmation for Existence of Hepatocyte Nuclear Factor-5
V. Challenges for the Future
Acknowledgments
References

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 to act 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 lead 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 liver-specific gene expression. It thus can be demonstrated that specific mutational changes in liver-enriched transcription factors lead to altered intermolecular interactions with the consequence of human disease. This review provides an overview of our current knowledge about liver-enriched transcription factors and their role in liver function and development. We review the basic principles of gene transcription, the role of liver-enriched transcription factors in liver gene regulation, and the classification of transcription factors by their DNA-binding domains.

0031-6997/02/5401-0129$03.00/0
PHARMACOLOGICAL REVIEWS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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