Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration

Aloia, Luigi and McKie, Mikel Alexander and Vernaz, Grégoire and Cordero-Espinoza, Lucía and Aleksieva, Niya and van den Ameele, Jelle and Antonica, Francesco and Font-Cunill, Berta and Raven, Alexander and Aiese Cigliano, Riccardo and Belenguer, German and Mort, Richard L. and Brand, Andrea H and Zernicka-Goetz, Magdalena and Forbes, Stuart J and Miska, Eric A and Huch, Meritxell (2019) Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration. Nature cell biology, 21 (11). pp. 1321-1333. ISSN 1465-7392

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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.