Liver‐enriched transcription factors and hepatocyte differentiation

Abstract

Liver-specific gene expression in adult hepatocytes relies on four families of evolutionary conserved transcription factors that are liver-enriched but not restricted to this tissue. These factors function in unique combinations, often synergistically, to stimulate cell-specific transcription. Each family is composed of several members displaying similar, if not identical, DNA recognition properties and sharing structural homology in their DNA binding domains. The homo- and heterodimerization between members of a particular transcription factor family adds an additional level of complexity in gene regulation. The consequences of inactivating different family members in the mouse by homologous recombination, together with recent studies of their regulation, suggest a model for liver differentiation involving a regulatory network rather than a completely hierarchical genetic circuitry. These studies also indicate that individual regulators appear to serve multiple developmental functions. Their possible role in the progression through different stages of hepatic cell commitment and differentiation is discussed.

A Crucial Role of Hepatocyte Nuclear Factor-4 Expression in the Differentiation of Human Ductular Hepatocytes

“…The differentiation is regulated by cell type-specific gene expression, which is controlled by distinct sets of transcription factors including HNFs (Cereghini, 1996;Darlington, 1999). The present study showed that normal human hepatocytes express HNF-4␣, whereas BEC do not, suggesting that HNF-4␣ plays a crucial role in the maintenance of normal hepatocyte function.…”

“…Transcription factors are generally controlled at two different levels, namely concentration and activity, each of which can be modulated in a variety of ways (Cereghini, 1996;Darlington, 1999). It is interesting to note that the level of the HNF expression in residual hepatocytes was low compared with that in ductular hepatocytes or regenerative hepatocytes.…”

“…Hepatocyte nuclear factors (HNFs) participate in the expression of liverspecific genes and play an important role in liver development and the functional maturation of hepatocytes (Calkhoven and Ab, 1996;Cereghini, 1996;Darlington, 1999;Kuo et al, 1992). If ductular structures are derived from liver progenitor cells and follow the course of differentiation into matured hepatocytes, they may express HNFs as seen in the development of the liver.…”

Signalling cross-talk between hepatocyte nuclear factor 4α and growth-hormone-activated STAT5b

“…HNF4α regulates the expression of genes in liver, both directly and indirectly, through interaction with other HNFs, including the variant homeodomain protein HNF1α, C/EBPs (CCAAT/enhancerbinding proteins), HNF3 winged helix factors and the one-cut homeoprotein, HNF6 [4]. These HNFs are, in turn, regulated through a complex transcriptional-control hierarchy that determines the relative expression and activity of other HNF family members.…”

Transcription factor HNF-6/OC-1 inhibits the stimulation of theHNF-3?/Foxa1 gene by TGF-? in mouse liver

“…[1][2][3] It comprises factors from several families that have been identified through biochemical and genetic studies. These include the CCAAT/enhancer binding proteins, the proline acidrich factors, the homeodomain proteins of the hepatocyte nuclear factor (HNF)-1 family, winged helix proteins (HNF-3/FoxA), nuclear receptors (HNF-4, LXR, FXR and FTF/hB1F/CPF families), and the Onecut (OC) factors (HNF-6/OC-1, OC-2 and OC-3).…”