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EZH2, JMJD3, and UTX epigenetically regulate hepatic plasticity inducing retro-differentiation and proliferation of liver cells.
- Source :
-
Cell death & disease [Cell Death Dis] 2019 Jul 08; Vol. 10 (7), pp. 518. Date of Electronic Publication: 2019 Jul 08. - Publication Year :
- 2019
-
Abstract
- Modification of histones by lysine methylation plays a role in many biological processes, and it is dynamically regulated by several histone methyltransferases and demethylases. The polycomb repressive complex contains the H3K27 methyltransferase EZH2 and controls dimethylation and trimethylation of H3K27 (H3K27me2/3), which trigger gene suppression. JMJD3 and UTX have been identified as H3K27 demethylases that catalyze the demethylation of H3K27me2/3, which in turns lead to gene transcriptional activation. EZH2, JMJD3 and UTX have been extensively studied for their involvement in development, immune system, neurodegenerative disease, and cancer. However, their role in molecular mechanisms underlying the differentiation process of hepatic cells is yet to be elucidated. Here, we show that EZH2 methyltransferase and JMJD3/UTX demethylases were deregulated during hepatic differentiation of human HepaRG cells resulting in a strong reduction of H3K27 methylation levels. Inhibition of JMJD3 and UTX H3K27 demethylase activity by GSK-J4 epi-drug reverted phenotype of HepaRG DMSO-differentiated cells and human primary hepatocytes, drastically decreasing expression of hepatic markers and inducing cell proliferation. In parallel, inhibition of EZH2 H3K27me3 activity by GSK-126 epi-drug induced upregulation of hepatic markers and downregulated the expression of cell cycle inhibitor genes. To conclude, we demonstrated that modulation of H3K27 methylation by inhibiting methyl-transferase and dimethyl-transferase activity influences the differentiation status of hepatic cells, identifying a possible new role of EZH2, JMJD3 and UTX epi-drugs to modulate hepatic cell plasticity.
- Subjects :
- Benzazepines pharmacology
Biomarkers metabolism
Cell Line
Cell Proliferation drug effects
Cells, Cultured
Gene Expression Profiling
Gene Expression Regulation, Developmental drug effects
Hepatocytes drug effects
Hepatocytes metabolism
Histones metabolism
Humans
Indoles pharmacology
Lysine metabolism
Methylation
Principal Component Analysis
Pyridones pharmacology
Pyrimidines pharmacology
Cell Differentiation drug effects
Enhancer of Zeste Homolog 2 Protein metabolism
Epigenesis, Genetic drug effects
Histone Demethylases metabolism
Jumonji Domain-Containing Histone Demethylases metabolism
Liver cytology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 10
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 31285428
- Full Text :
- https://doi.org/10.1038/s41419-019-1755-2