Identifying the epigenetic regulatory mechanisms that drive the response of liver ductal cells to damage

• Applicants: Dr. Andreas Dahl; Dr. Meritxell Huch
• Subject Area: Developmental Biology ; Cell Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 514150034

Despite recent advances, the principles that regulate tissue regeneration and how their deregulation leads to disease remain largely unknown. The liver represents an outstanding model of quiescent tissue where to investigate the mechanisms of regeneration and their changes in disease. It excels in its regenerative capacity upon damage. It has a virtually unlimited capacity to regenerate following amputation. However, its regeneration capacity is limited upon toxic injury (e.g. drugs, alcohol), leading to scaring or cancer. A key question is: what are the molecular mechanisms that regulate repair vs disease in the liver? During liver regeneration, differentiated epithelial cells (hepatocytes and ductal cells) switch their state to activate proliferation and differentiation. We recently demonstrated that during this switch from quiescence to activation adult liver ductal cells undergo profound epigenetic reprogramming with >3000 genes changing their methylation profile. However, only some cells proliferate, whereas others remain quiescent. We hypothesize that the intrinsic epigenetic state of the cell could determine its response to damage, with some cells having epigenetic states that predispose (primed) to regenerate vs other states that prevent cells from regenerating. In addition, given the massive epigenetic rewiring required for switching to an active state, it is likely that these changes are not fully restored, and some loci retain “memory” of a damage-repair event, that alters the potential for future re-activation of the cell. Hence, we also hypothesize that through such “memory” cells exposed to repetitive damage could exhaust their ability to regenerate, leading to disease. Here we will aim to identify the regulatory elements (e.g. transcription factors, epigenetic regulators) and molecular pathways that change during regeneration and that could drive the differences between regeneration and disease. Specifically, we will: Aim 1, obtain time-resolved maps of transcriptional and epigenetic profiles of the same liver cell during the different phases of the damage-repair response (from quiescence to recovery), in 3 different types of liver damage models: (1): a damage-repair model; (2) a model of reduced regeneration and (3) a model of unlimited regeneration. Aim 2, identify candidate genes / genomic loci / pathways involved in repair vs disease, as well as loci that retain “memory” of a regeneration event, by comparing the transcriptional and epigenetic landscape of the cells at different damage models and different phases of the damage-repair response. Aim3, validate some of the candidates obtained in Aim2 in liver organoids, which we have pioneered over the years, and in vivo, in animal models of liver damage. An in-depth understanding of the molecular mechanisms driving tissue regeneration and their deregulation in disease holds the potential to uncover new principles of liver biology.

• DFG Programme: Research Grants