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Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration

Research output: Contribution to journalJournal articlepeer-review

  • Luigi Aloia
  • Mikel Alexander McKie
  • Grégoire Vernaz
  • Lucía 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
<mark>Journal publication date</mark>4/11/2019
<mark>Journal</mark>Nature cell biology
Issue number11
Number of pages13
Pages (from-to)1321-1333
Publication StatusPublished
Early online date4/11/19
<mark>Original language</mark>English


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.