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Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration
AU - Aloia, Luigi
AU - McKie, Mikel Alexander
AU - Vernaz, Grégoire
AU - Cordero-Espinoza, Lucía
AU - Aleksieva, Niya
AU - van den Ameele, Jelle
AU - Antonica, Francesco
AU - Font-Cunill, Berta
AU - Raven, Alexander
AU - Aiese Cigliano, Riccardo
AU - Belenguer, German
AU - Mort, Richard L.
AU - Brand, Andrea H
AU - Zernicka-Goetz, Magdalena
AU - Forbes, Stuart J
AU - Miska, Eric A
AU - Huch, Meritxell
PY - 2019/11/4
Y1 - 2019/11/4
N2 - 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.
AB - 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.
U2 - 10.1038/s41556-019-0402-6
DO - 10.1038/s41556-019-0402-6
M3 - Journal article
C2 - 31685987
VL - 21
SP - 1321
EP - 1333
JO - Nature cell biology
JF - Nature cell biology
SN - 1465-7392
IS - 11
ER -