Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Bile Ducts / cytology
  • Bile Ducts / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • DNA Methylation
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Epigenesis, Genetic*
  • Epigenome*
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Female
  • Gene Expression Profiling
  • Hippo Signaling Pathway
  • Liver / cytology
  • Liver / metabolism*
  • Liver Regeneration / genetics*
  • Male
  • Mice, Transgenic
  • Organoids / cytology
  • Organoids / metabolism*
  • Primary Cell Culture
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Signal Transduction
  • Transcriptome*
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • TET1 protein, mouse
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • Protein Serine-Threonine Kinases