Edinburgh Research Explorer

Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration

Research output: Contribution to journalArticle

  • Luigi Aloia
  • Mikel Alexander Mckie
  • Gregoire Vernaz
  • Lucia Cordero-Espinoza
  • Niya Aleksieva
  • Jelle van den Ameele
  • Francesco Antonica
  • Berta Font-Cunill
  • Alexander Raven
  • Riccardo Aiese Cigliano
  • German Belenguer
  • Richard Mort
  • Andrea H. Brand
  • Magdalena Zernicka-Goetz
  • Stuart Forbes
  • Eric A. Miska
  • Meritxell Huch

Related Edinburgh Organisations

Original languageEnglish
JournalNature Cell Biology
DOIs
Publication statusPublished - 4 Nov 2019

Abstract

Upon severe or chronic liver injury, adult ductal cells (cholangiocytes) contribute to regeneration by restoring both hepatocytes and cholangiocytes. Recently, we 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, during organoid initiation and in vivo following tissue damage, ductal cells undergo a transient, genome-wide, remodelling of their transcriptome and epigenome. 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. 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.
The adult liver exhibits low physiological turnover, however it has an efficient regenerative ability following damage. Upon tissue injury, if hepatocyte proliferation is compromised, resident, lineage-restricted ductal cells (cholangiocytes) acquire cellular plasticity to regenerate both, cholangiocytes and hepatocytes1-9. Similarly, in vitro, ductal cells grown as clonal organoids become bi-potential, express stem/progenitor markers, including Lgr54,10,11, Foxl17 and Trop212, and differentiate into both ductal and hepatocyte-like cells in vitro and mature hepatocytes in vivo, upon transplantation4,13,14. However, the molecular mechanisms by which adult committed cells exit their lineage-restricted state, initiate proliferating organoids and respond to damage by generating both ductal cells and hepatocytes remain largely unknown. During development, epigenetic mechanisms are imposed to ensure that differentiated cells remain lineage-restricted15. In mammals, 5-methylcytosine (5mC) is the most common DNA modification and is associated to gene repression at promoter and enhancer level16-20. DNA demethylation might occur passively, due to loss of DNA methylation maintenance during replication or via the conversion of 5mC to 5hmC by the Ten-eleven translocation (TET) family of methylcytosine dioxygenase enzymes21,22, which results in dilution of 5hmC through DNA replication23. Moreover, cytosine demethylation can be achieved by a replication-independent mechanism mediated by TETs, whereby 5mC is converted to 5hmC, which can be further oxidized and replaced with an unmodified cytosine24,25.Erasure of 5mC and TET1 activity are essential for resetting the genome for pluripotency, germ-cell specification, imprinting and somatic cell reprogramming26-30. During development and postnatal life, Tet1 is essential to maintain the intestinal stem cell pool31, while Tet2 and Tet3 are required to induce postnatal demethylation in hepatocytes32. However, whether epigenetic mechanisms and/or DNA-90 methylation/hydroxymethylation play a role in the acquisition of cellular plasticity in adult differentiated cells during the regenerative response has not been investigated yet. Here, we report that in the liver, during the response to tissue damage, adult resident ductal cells undergo a genome-wide remodelling of their transcriptional and methylome/hydroxymethylome landscapes in the absence of ectopic genetic 96 manipulation. We identify TET1-mediated hydroxymethylation and its downstream regulation of ErbB/MAPK and YAP/Hippo signalling pathways as one of the epigenetic mechanisms required for lineage-restricted ductal cells to acquire cellular plasticity, establish liver organoids and elicit a full regenerative response.

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