Publication Date
5-18-2020
Journal
Nature Communications
DOI
10.1038/s41467-020-16300-x
PMID
32424153
PMCID
PMC7235048
PubMedCentral® Posted Date
5-18-2020
Published Open-Access
no
Keywords
Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Bile Duct Neoplasms, Bile Ducts, Cell Differentiation, Cell Lineage, Cell Proliferation, Cholangiocarcinoma, Down-Regulation, Hepatocytes, Liver, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Phenotype, Promoter Regions, Genetic, Protein Binding, Regeneration, SOX9 Transcription Factor, Spheroids, Cellular, Stem Cells, Up-Regulation, Transdifferentiation, Regeneration
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.
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Biology Commons, Medical Anatomy Commons, Oncology Commons
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