Transcriptomic and epigenetic mechanisms controlling cholangiocyte transdifferentiation into hepatocytes

Recent reports proposed the transdifferentiation of cholangiocytes into hepatocytes as the main regenerative process occurring during chronic liver diseases. However, the mechanisms involved remain to be fully uncovered. Our study addresses this knowledge gap in humans. We first showed that cholangiocyte organoids derived from different liver lobes have equivalent capacity to produce cells expressing hepatocyte markers. Furthermore, detailed single-nucleus analyses of transcriptomic and epigenetic signatures in cholangiocytes transdifferentiating into hepatocytes in vitro revealed that this process involves genome-wide chromatin reorganization, confirming that cellular plasticity is closely linked to epigenetic regulation. Finally, these experiments indicated the expression of HNF4G in transdifferentiating cholangiocytes, while functional studies established that HNF4G upregulation is sufficient to increase the expression of hepatocyte markers in cholangiocytes. Thus, manipulating HNF4G expression can act as a potential therapeutic target for promoting liver plasticity and regeneration in end-stage liver disease.