TFEB regulates murine liver cell fate during development and regeneration

Nunzia Pastore (), Tuong Huynh, Niculin J. Herz, Alessia Calcagni’, Tiemo J. Klisch, Lorenzo Brunetti, Kangho Ho Kim, Marco De Giorgi, Ayrea Hurley, Annamaria Carissimo, Margherita Mutarelli, Niya Aleksieva, Luca D’Orsi, William R. Lagor, David D. Moore, Carmine Settembre, Milton J. Finegold, Stuart J. Forbes and Andrea Ballabio ()
Additional contact information
Nunzia Pastore: Texas Children Hospital
Tuong Huynh: Texas Children Hospital
Niculin J. Herz: Texas Children Hospital
Alessia Calcagni’: Texas Children Hospital
Tiemo J. Klisch: Texas Children Hospital
Lorenzo Brunetti: Baylor College of Medicine
Kangho Ho Kim: Baylor College of Medicine
Marco De Giorgi: Baylor College of Medicine
Ayrea Hurley: Baylor College of Medicine
Annamaria Carissimo: Telethon Institute of Genetics and Medicine (TIGEM)
Margherita Mutarelli: Telethon Institute of Genetics and Medicine (TIGEM)
Niya Aleksieva: University of Edinburgh
Luca D’Orsi: Telethon Institute of Genetics and Medicine (TIGEM)
William R. Lagor: Baylor College of Medicine
David D. Moore: Baylor College of Medicine
Carmine Settembre: Telethon Institute of Genetics and Medicine (TIGEM)
Milton J. Finegold: Baylor College of Medicine
Stuart J. Forbes: University of Edinburgh
Andrea Ballabio: Texas Children Hospital

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes. However, the signaling pathways implicated in the differentiation of LPCs are still incompletely understood. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is known to be involved in osteoblast and myeloid differentiation, but its role in lineage commitment in the liver has not been investigated. Here we show that during development and upon regeneration TFEB drives the differentiation status of murine LPCs into the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation. Genetic interaction studies show that Sox9, a marker of precursor and biliary cells, is a direct transcriptional target of TFEB and a primary mediator of its effects on liver cell fate. In summary, our findings identify an unexplored pathway that controls liver cell lineage commitment and whose dysregulation may play a role in biliary cancer.

Date: 2020
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DOI: 10.1038/s41467-020-16300-x

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