Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration

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

Institutions:

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: https://www.nature.com/articles/s41556-019-0402-6

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.