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Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration

Research output: Contribution to journalJournal article

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  • 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
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<mark>Journal publication date</mark>4/11/2019
<mark>Journal</mark>Nature cell biology
Issue number11
Volume21
Number of pages13
Pages (from-to)1321-1333
Publication statusPublished
Early online date4/11/19
Original languageEnglish

Abstract

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.