Authors: L. Aloia, M. A. McKie, G. Vernaz, L. Cordero-Espinoza, N. Aleksieva, J. van den Ameele, F. Antonica, B. Font-Cunill, A. Raven, R. Aiese Cigliano, G. Belenguer, R. L. Mort, A. H. Brand, M. Zernicka-Goetz, S. J. Forbes, E. A. Miska & M. Huch


  • The Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, UK
  • Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
  • Wellcome Trust – Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK
  • Department of Genetics, University of Cambridge, Cambridge, UK
  • Wellcome Sanger Institute, Hinxton, UK
  • MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
  • Sequentia Biotech SL, Barcelona, Spain
  • Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
  • Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Bailrigg, Lancaster, UK
  • Division of Biology and Biological Engineering, Caltech, Pasadena, CA, USA

Publication: Nature Cell Biology

Date: November 2019

Full paper:

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.

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