Format

Send to

Choose Destination
Nat Cell Biol. 2019 Nov;21(11):1321-1333. doi: 10.1038/s41556-019-0402-6. Epub 2019 Nov 4.

Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration.

Author information

1
The Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, UK.
2
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
3
Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.
4
Department of Genetics, University of Cambridge, Cambridge, UK.
5
Wellcome Sanger Institute, Hinxton, UK.
6
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
7
Sequentia Biotech SL, Barcelona, Spain.
8
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
9
Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Bailrigg, Lancaster, UK.
10
Division of Biology and Biological Engineering, Caltech, Pasadena, CA, USA.
11
The Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, UK. huch@mpi-cbg.de.
12
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK. huch@mpi-cbg.de.
13
Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK. huch@mpi-cbg.de.
14
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany. huch@mpi-cbg.de.

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.

PMID:
31685987
PMCID:
PMC6940196
[Available on 2020-05-01]
DOI:
10.1038/s41556-019-0402-6
[Indexed for MEDLINE]

Publication type, MeSH terms, Substances, Grant support

Publication type

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center