Cascades of transcription regulation during liver regeneration

Abstract

An increasing demand for new strategies in cancer prevention and regenerative medicine requires a better understanding of molecular mechanisms that control cell proliferation in tissue-specific manner. Regenerating liver is a unique model allowing use of biochemical, genetic, and engineering tools to uncover molecular mechanisms and improve treatment of hepatic cancers, liver failure, and fibrotic disease. Molecular mechanisms of liver regeneration involve extra- and intracellular factors to activate transcription of genes normally silenced in quiescent liver. While many upstream signaling pathways of the regenerating liver have been extensively studied, our knowledge of the downstream effectors, transcription factors (TFs), remains limited. This review describes consecutive engagement of pre-existing and de novo synthesized TFs, as cascades that regulate expression of growth-related and metabolic genes during liver regeneration after partial hepatectomy in mice. Several previously recognized regulators of regenerating liver are described in the light of recently identified co-activator and co-repressor complexes that interact with primary DNA-binding TFs. Published results of gene expression and chromatin immunoprecipitation analyses, as well as studies of transgenic mouse models, are used to emphasize new potential regulators of transcription during liver regeneration. Finally, a more detailed description of newly identified transcriptional regulators of liver regeneration illustrates the tightly regulated balance of proliferative and metabolic responses to partial hepatectomy.

Figure 1. Transcriptional cascades during liver regeneration

The progression of liver regeneration is mediated through stages of the cell cycle (G₀: left; G₁, S, G₂, M: right) by transcription factor activities and gene expression (see text for details) in hepatocytes (H – boxes, foreground). Structural elements of the liver (PV – portal vein; BD – bile duct; CV – central vein; HA – hepatic artery; HC – Hering’s canal; S – sinusoid; ECM – extracellular matrix; background), and PH-induced regulators (1: LPS, ICAM, complement factors, insulin, acetycholine, norepinephrine, EGF, xenobiotics; 2: Il6 and TNFα; 3: VEGF; 4: HGF; 5: TGFβ; 6: bile acids) secreted by and/or signaling to non-parenchymal cells of the liver (CH – cholangiocyte; EC – endothelial cell; KC – Kuppfer cell; SC – stellate cell), play specific roles in induction of transcription cascades during liver regeneration.