Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration

Luigi Aloia, Mikel Alexander Mckie, Gregoire Vernaz, Lucia Cordero-Espinoza, Niya Aleksieva, Jelle van den Ameele, Francesco Antonica, Berta Font-Cunill, Alexander Raven, Riccardo Aiese Cigliano, German Belenguer, Richard L. Mort, Andrea H. Brand, Magdalena Zernicka-Goetz, Stuart J. Forbes, Eric A. Miska, Meritxell Huch

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)1321–1333
Number of pages13
JournalNature Cell Biology
Volume21
Issue number11
Early online date4 Nov 2019
DOIs
Publication statusPublished - Nov 2019

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