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.
Highlights
The liver participates in a variety of crucial biological processes such as hemopoiesis during embryonic life and metabolism, glycogen storage, detoxification, plasma protein secretion, acute phase reaction, and hormonal homeostasis in adulthood
The gene expression pattern of fully differentiated hepatocytes is generated by multiple regulatory signals involving the sequential action of hepatic transcription factors during embryonic and postnatal development
The process is initiated by pioneer factors that bind to and destabilize the chromatin at gene regulatory loci, which allows for the recruitment of additional transcription factors necessary for the activation of the target genes
Summary
The liver participates in a variety of crucial biological processes such as hemopoiesis during embryonic life and metabolism, glycogen storage, detoxification, plasma protein secretion, acute phase reaction, and hormonal homeostasis in adulthood. The major cell type of the liver is the hepatocyte, which arises from endodermal precursors through a complex multistep differentiation process. The gene expression pattern of each intermediate cell type is generated by the action of transcription factors, which bind to the regulatory regions of their target genes and activate transcription at specific times during development. Developmental cell fate decisions are determined by cell-to-cell communication and the action of complex signaling pathways. Signaling molecules exert their function through the modulation of transcription factor activity, either directly or indirectly. We summarize current knowledge about the function of major transcription factors involved in different stages of liver development. We present our current understanding of the regulatory mechanisms of developmental gene activation
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