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.

Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration / Aloia, Luigi; Mckie, Mikel Alexander; Vernaz, Grégoire; Cordero-Espinoza, Lucía; Aleksieva, Niya; van den Ameele, Jelle; Antonica, Francesco; Font-Cunill, Berta; Raven, Alexander; Aiese Cigliano, Riccardo; Belenguer, German; Mort, Richard L; Brand, Andrea H; Zernicka-Goetz, Magdalena; Forbes, Stuart J; Miska, Eric A; Huch, Meritxell. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - 21:11(2019), pp. 1321-1333. [10.1038/s41556-019-0402-6]

Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration

Antonica, Francesco;
2019-01-01

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.
2019
11
Aloia, Luigi; Mckie, Mikel Alexander; Vernaz, Grégoire; Cordero-Espinoza, Lucía; Aleksieva, Niya; van den Ameele, Jelle; Antonica, Francesco; Font-Cunill, Berta; Raven, Alexander; Aiese Cigliano, Riccardo; Belenguer, German; Mort, Richard L; Brand, Andrea H; Zernicka-Goetz, Magdalena; Forbes, Stuart J; Miska, Eric A; Huch, Meritxell
Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration / Aloia, Luigi; Mckie, Mikel Alexander; Vernaz, Grégoire; Cordero-Espinoza, Lucía; Aleksieva, Niya; van den Ameele, Jelle; Antonica, Francesco; Font-Cunill, Berta; Raven, Alexander; Aiese Cigliano, Riccardo; Belenguer, German; Mort, Richard L; Brand, Andrea H; Zernicka-Goetz, Magdalena; Forbes, Stuart J; Miska, Eric A; Huch, Meritxell. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - 21:11(2019), pp. 1321-1333. [10.1038/s41556-019-0402-6]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/352844
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