YAP integrates the regulatory Snail/HNF4α circuitry controlling epithelial/hepatocyte differentiation.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Cell Cycle Proteins
/ genetics
Cell Differentiation
/ genetics
Cell Line, Tumor
Down-Regulation
Epithelial Cells
/ cytology
Epithelial-Mesenchymal Transition
/ genetics
Gene Silencing
Hepatocyte Nuclear Factor 4
/ genetics
Hepatocytes
/ cytology
Humans
Mice
Promoter Regions, Genetic
Protein Binding
Snail Family Transcription Factors
/ genetics
Transcription Factors
/ genetics
Up-Regulation
YAP-Signaling Proteins
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
10 10 2019
10 10 2019
Historique:
received:
07
02
2019
accepted:
24
06
2019
revised:
29
05
2019
entrez:
12
10
2019
pubmed:
12
10
2019
medline:
28
8
2020
Statut:
epublish
Résumé
Yes-associated protein (YAP) is a transcriptional co-factor involved in many cell processes, including development, proliferation, stemness, differentiation, and tumorigenesis. It has been described as a sensor of mechanical and biochemical stimuli that enables cells to integrate environmental signals. Although in the liver the correlation between extracellular matrix elasticity (greatly increased in the most of chronic hepatic diseases), differentiation/functional state of parenchymal cells and subcellular localization/activation of YAP has been previously reported, its role as regulator of the hepatocyte differentiation remains to be clarified. The aim of this study was to evaluate the role of YAP in the regulation of epithelial/hepatocyte differentiation and to clarify how a transducer of general stimuli can integrate tissue-specific molecular mechanisms determining specific cell outcomes. By means of YAP silencing and overexpression we demonstrated that YAP has a functional role in the repression of epithelial/hepatocyte differentiation by inversely modulating the expression of Snail (master regulator of the epithelial-to-mesenchymal transition and liver stemness) and HNF4α (master regulator of hepatocyte differentiation) at transcriptional level, through the direct occupancy of their promoters. Furthermore, we found that Snail, in turn, is able to positively control YAP expression influencing protein level and subcellular localization and that HNF4α stably represses YAP transcription in differentiated hepatocytes both in cell culture and in adult liver. Overall, our data indicate YAP as a new member of the HNF4/Snail epistatic molecular circuitry previously demonstrated to control liver cell state. In this model, the dynamic balance between three main transcriptional regulators, that are able to control reciprocally their expression/activity, is responsible for the induction/maintenance of different liver cell differentiation states and its modulation could be the aim of therapeutic protocols for several chronic liver diseases.
Identifiants
pubmed: 31601778
doi: 10.1038/s41419-019-2000-8
pii: 10.1038/s41419-019-2000-8
pmc: PMC6787001
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Cell Cycle Proteins
0
Hepatocyte Nuclear Factor 4
0
Snail Family Transcription Factors
0
Transcription Factors
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
Yap1 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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