Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration.

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McKie, Mikel Alexander  ORCID logo  https://orcid.org/0000-0002-1711-4034
Cordero-Espinoza, Lucía 
Aleksieva, Niya 

Following severe or chronic liver injury, adult ductal cells (cholangiocytes) contribute to regeneration by restoring both hepatocytes and cholangiocytes. We recently showed that ductal cells clonally expand as self-renewing liver organoids that retain their differentiation capacity into both hepatocytes and ductal cells. However, the molecular mechanisms by which adult ductal-committed cells acquire cellular plasticity, initiate organoids and regenerate the damaged tissue remain largely unknown. Here, we describe that ductal cells undergo a transient, genome-wide, remodelling of their transcriptome and epigenome during organoid initiation and in vivo following tissue damage. TET1-mediated hydroxymethylation licences differentiated ductal cells to initiate organoids and activate the regenerative programme through the transcriptional regulation of stem-cell genes and regenerative pathways including the YAP-Hippo signalling. Our results argue in favour of the remodelling of genomic methylome/hydroxymethylome landscapes as a general mechanism by which differentiated cells exit a committed state in response to tissue damage.

Adaptor Proteins, Signal Transducing, Animals, Bile Ducts, Cell Cycle Proteins, DNA Methylation, DNA-Binding Proteins, Epigenesis, Genetic, Epigenome, Epithelial Cells, Female, Gene Expression Profiling, Hippo Signaling Pathway, Liver, Liver Regeneration, Male, Mice, Transgenic, Organoids, Primary Cell Culture, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins, Signal Transduction, Transcriptome, YAP-Signaling Proteins
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Nat Cell Biol
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Springer Science and Business Media LLC
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Wellcome Trust (104151/Z/14/Z)
European Commission Horizon 2020 (H2020) Research Infrastructures (RI) (668350)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (702585)
National Centre for the Replacement Refinement and Reduction of Animals in Research (NC/R001162/1)
Wellcome Trust (103792/Z/14/Z)
Wellcome Trust (105839/Z/14/Z)
Royal Society (RP150061)
Wellcome Trust (092096/Z/10/Z)
Cancer Research UK (18583)
Wellcome Trust (104640/Z/14/Z)
Cancer Research Uk (None)
European Research Council (669198)
Medical Research Council (MC_PC_12009)
RCUK Cancer Research UK ERC H2020 Wellcome Trust