Transcription Control of Liver Development

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.

Loss of liver function in chronic liver disease: An identity crisis

“…Their progressive involvement culminates at the post-natal level with the establishment of the characteristic transcriptome of the adult hepatocyte. The FOXA family of proteins, composed by three members FOXA1, FOXA2 and FOXA3 (also known as HNF3, HNF3 and HNF3, respectively), is expressed early during endoderm patterning and is essential for liver development [6,8]. Another set of regulatory proteins almost concomitantly involved in hepatoblast specification is the GATA family of TFs, particularly GATA4 and GATA6.…”

“…To perform these complex and spatially coordinated functions hepatocytes must express a large complement of enabling genes. This gene expression signature is progressively established from early hepatic development through cell-to-cell signalling and a network of key transcription factors (TFs) and their activation or repression complexes, that shape up liver-specific gene expression [6]. After birth, an increasingly complex set of cross-regulated TFs, plus signalling systems such as WNT and Notch, and splicing regulators (SR), define the liver zonal architecture and consolidate mature hepatocellular function [2,[6][7][8]].…”

“…This gene expression signature is progressively established from early hepatic development through cell-to-cell signalling and a network of key transcription factors (TFs) and their activation or repression complexes, that shape up liver-specific gene expression [6]. After birth, an increasingly complex set of cross-regulated TFs, plus signalling systems such as WNT and Notch, and splicing regulators (SR), define the liver zonal architecture and consolidate mature hepatocellular function [2,[6][7][8]]. An intricate system of signals, TFs and epigenetic mechanisms secure the preservation of the liverspecific gene expression pattern (i.e.…”

Short Linear Motifs Orchestrate Functioning of Human Proteins during Embryonic Development, Redox Regulation, and Cancer

“…These domains provide the involvement of TRIM proteins transcriptional regulation, cytoskeletal organization, epithelial development, cell adhesion, and immune response [ 22 ]. Another retrieved transcription factor, HHEX, is involved in cell growth and differentiation, hepatic and pancreatic development, and anterior–posterior pattern specification via the Wnt signaling pathway [ 23 ]. Additionally, HHEX has been associated with type 2 diabetes, whereas zinc finger proteins are linked to the progression of various cancers [ 63 , 64 , 65 ].…”

Comparative Transcriptome Analysis Provides Novel Molecular Events for the Differentiation and Maturation of Hepatocytes during the Liver Development of Zebrafish

“…Genome-wide characterization of ESC-derived hepatocyte-like cells indicated that some genes are associated with metabolic processes such as small molecule metabolic processes or secondary metabolic processes [ 64 ]. Some transcription factors, such as FOXA1/2/3, HNF4α, and CEBPA can maintain hepatocyte maturation through a combined action [ 65 ]. In this study, we found that, in addition to signaling pathways for cell proliferation and DNA replication, newly enriched signaling pathways in hepatocytes between 72 to 96 hpf include metabolisms of pyrimidine, purine, nicotinate and nicotinamide, caffeine, glycine, serine and threonine, ABC transporters, and p53 signaling, which are known to function in metabolisms of lipid, protein and energy, cellular secretion, and detoxification.…”