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Review
. 2021 Aug 8;10(8):2026.
doi: 10.3390/cells10082026.

Transcription Control of Liver Development

Evangelia C Tachmatzidi  1   2 , Ourania Galanopoulou  1   2 , Iannis Talianidis  1
Affiliations
Review

Transcription Control of Liver Development

Evangelia C Tachmatzidi et al. Cells. .

Abstract

During liver organogenesis, cellular transcriptional profiles are constantly reshaped by the action of hepatic transcriptional regulators, including FoxA1-3, GATA4/6, HNF1α/β, HNF4α, HNF6, OC-2, C/EBPα/β, Hex, and Prox1. These factors are crucial for the activation of hepatic genes that, in the context of compact chromatin, cannot access their targets. The initial opening of highly condensed chromatin is executed by a special class of transcription factors known as pioneer factors. They bind and destabilize highly condensed chromatin and facilitate access to other "non-pioneer" factors. The association of target genes with pioneer and non-pioneer transcription factors takes place long before gene activation. In this way, the underlying gene regulatory regions are marked for future activation. The process is called "bookmarking", which confers transcriptional competence on target genes. Developmental bookmarking is accompanied by a dynamic maturation process, which prepares the genomic loci for stable and efficient transcription. Stable hepatic expression profiles are maintained during development and adulthood by the constant availability of the main regulators. This is achieved by a self-sustaining regulatory network that is established by complex cross-regulatory interactions between the major regulators. This network gradually grows during liver development and provides an epigenetic memory mechanism for safeguarding the optimal expression of the regulators.

Keywords: bookmarking; chromatin; development; gene expression; liver; transcription factor.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Liver development. Liver organogenesis begins in the definitive endoderm at E8.5. BMP signals from the septum transversum and FGF signals from the adjacent heart induce cells in the ventral foregut endoderm to differentiate towards hepatoblasts. After hepatoblast specification, the hepatic epithelium is re-organized and forms the liver diverticulum. By E9.5, hepatoblasts are able to migrate into the septum transversum mesenchyme and produce the liver bud. Between E9.5 to E15, hepatoblasts expand and the liver bud grows. At these stages, the formation of canalicular structures and the appearance of endothelial sinusoid cells become detectable. Around E13, hepatoblasts begin their differentiation into hepatocytes or cholangiocytes, followed by the formation of the zonal structures as specified by the central vein and portal triad regions.
Figure 2
Figure 2
Mechanism of pioneer factor activity, transcriptional activation, and bookmarking. The initial binding of a pioneer factor to its target sites occurs in highly condensed chromatin and results in increased chromatin accessibility. The progressive recruitment of chromatin modifiers and the stable or transient binding of other transcription factors lead to the gradual deposition of activating histone modifications and the broadening of active chromatin domains. The resulting permissive chromatin state facilitates the assembly of the pre-initiation complex (PIC) and promotes transcriptional initiation. Loci that are postnatally silenced retain transcription factors on their promoters, keeping them competent for re-activation under certain conditions. PF: pioneer factor; TF: transcription factor.
Figure 3
Figure 3
Schematic diagram of the transcription factor network during liver development. During the initial specification, early embryonic, and hepatoblast stages, the cross-regulatory interactions are limited and are dominated by single-input and double-input motifs. Hepatoblasts are bipotential cells, which give rise to hepatocytes and cholangiocytes. The loss of C/EBPα in cholangiocytes leads to the increased expression of HNF6 and HNF1β. The regulatory interactions are reorganized in hepatocytes and form a network, which becomes more complex as differentiation proceeds to the adult stages. The increased number of transcription factors on the individual promoters confer functional redundancy and network stability.
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