The role of the activin cistrome in liver progenitor cell-mediated liver regeneration

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Activin response element (ARE) are localized in the promoters of master differentiation genes. The sequence motif is a specific binding site for the SMAD4-SMAD2/3-FOXH1 complex, involved in the regulation of embryonic stem cell (ESC) differentiation during organ development. Without extracellular signals, the entirety of ARE-directed gene expression, subsequently called the "activin cistrome", is blocked in ESC by repressive chromatin compacting factor HP1-lysine trimethylation on histone H3 complexes, thus holding ESC in a silent state. Quiescent ESC switch into differentiation mode once the activin cistrome is activated by signals from TGF- family members e.g. Nodal, activin and TGF-. Exposure of ESC to these cytokines results in the formation of complexes comprising TRIM33 and phosphorylated SMAD2 and SMAD3, which replace HP1 and uncover the ARE. Subsequently, the TGF--induced transcription factor complex SMAD4-SMAD2/3-FoxH1 binds to the activin response elements, and induces expression of master differentiation genes, initiating cell differentiation. In humans, liver progenitor cells (LPC), adult liver stem-like cells, play a crucial role in restoring liver mass and function in severe liver damage, e.g. cirrhosis, acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). Successful LPC-mediated liver regeneration requires rapid LPC differentiation into hepatocytes. It is unknown to date if LPC differentiation into hepatocytes is governed by the activin cistrome. Preliminary data for this project show that ALF or ACLF patients with a negative outcome, i.e. liver transplantation or death, showed weak or undetectable hepatic expression of p-SMAD2, TRIM33 and FOXH1. In contrast, compensated cirrhotic patients express high levels of the three transcription factors in LPC and LPC-derived hepatocytes. In vitro study further showed that LPC-to-hepatocyte differentiation required SMAD2/3, TRIM33 and FOXH1. Thus, we hypothesize that activation of the activin cistrome by chromatin remodelling is crucial for LPC differentiation into hepatocytes. This project aims to elucidate (i) whether ARE-mediated LPC differentiation occurs in patients suffering from severe liver disease, e.g. cirrhosis, ALF and ACLF; (ii) if TGF- or activin or both induce activation of the activin cistrome in LPC under these severe circumstances; (iii) how activation of the activin cistrome impacts LPC differentiation into hepatocytes in vitro and (iv) if interfering with components of the activin cistrome influences LPC-mediated liver regeneration in animals. The project will define the role and molecular mechanisms of the activin cistrome in LPC-mediated liver regeneration and enable us to harness the regenerative power of these stem-like cells in events of cirrhosis and ALF/ACLF.