FIGURE 1.

Epigenetic mechanisms that allow cell-fate changes into bipotent liver progenitors. The adult liver is formed by two epithelial cell types, hepatocytes and cholangiocytes, which derive from a common bipotent embryonic progenitor, the hepatoblast. In the adulthood, in homeostatic conditions, the epigenetic landscape preserves cell-identity by maintaining chromatin conformations that stabilise the differentiated state (red). Upon injury, both adult hepatocytes and cholangiocytes can de-differentiate into bipotent liver progenitors that give rise to both liver epithelial cell types (green) and restore the liver epithelial compartment. This cell-fate change into progenitors is enabled by epigenetic mechanisms that determine permissive chromatin states, including increased chromatin accessibility mediated by Arid1a and the chromatin remodelling complex SWI/SNF (Li et al., 2019) and oxidation of 5-methycytosine (5mC) into 5-hydromethylcytosyne (5hmC) mediated by the methylcytosine dioxygenase TET1 (Aloia et al., 2019). Such permissive states facilitate the chromatin binding of the transcriptional machinery (e.g., YAP/TEAD) that promotes the establishment of liver progenitor identity. Importantly, dynamic epigenetic regulation allows liver epithelial cells to return to the homeostatic state once the injury is resolved and the tissue is repaired. In this regard, TET1 and 5hmC levels are only transiently enriched in cholangiocytes at early stages upon liver injury (Aloia et al., 2019), and histone deacetylation mediated by Hdac1 is required for differentiation of cholangiocyte progenitors into hepatocytes (Ko et al., 2019).