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Article

Genetic and Epigenetic Modification of Rat Liver Progenitor Cells via HNF4α Transduction and 5’ Azacytidine Treatment: An Integrated miRNA and mRNA Expression Profile Analysis

1
Department of In Vitro Toxicology and Dermato-cosmetology (IVTD), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, B-1090 Brussels, Belgium
2
Department of Gene Therapy and Regenerative Medicine (GTRM), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, B-1090 Brussels, Belgium
*
Author to whom correspondence should be addressed.
Equal first authors.
Equal senior authors.
Genes 2020, 11(5), 486; https://doi.org/10.3390/genes11050486
Received: 7 April 2020 / Revised: 27 April 2020 / Accepted: 28 April 2020 / Published: 29 April 2020
Neonatal liver-derived rat epithelial cells (rLEC) from biliary origin are liver progenitor cells that acquire a hepatocyte-like phenotype upon sequential exposure to hepatogenic growth factors and cytokines. Undifferentiated rLEC express several liver-enriched transcription factors, including the hepatocyte nuclear factors (HNF) 3β and HNF6, but not the hepatic master regulator HNF4α. In this study, we first investigated the impact of the ectopic expression of HNF4α in rLEC on both mRNA and microRNA (miR) level by means of microarray technology. We found that HNF4α transduction did not induce major changes to the rLEC phenotype. However, we next investigated the influence of DNA methyl transferase (DNMT) inhibition on the phenotype of undifferentiated naïve rLEC by exposure to 5′ azacytidine (AZA), which was found to have a significant impact on rLEC gene expression. The transduction of HNF4α or AZA treatment resulted both in significantly downregulated C/EBPα expression levels, while the exposure of the cells to AZA had a significant effect on the expression of HNF3β. Computationally, dysregulated miRNAs were linked to target mRNAs using the microRNA Target Filter function of Ingenuity Pathway Analysis. We found that differentially regulated miRNA–mRNA target associations predict ectopic HNF4α expression in naïve rLEC to interfere with cell viability and cellular maturation (miR-19b-3p/NR4A2, miR30C-5p/P4HA2, miR328-3p/CD44) while it predicts AZA exposure to modulate epithelial/hepatic cell proliferation, apoptosis, cell cycle progression and the differentiation of stem cells (miR-18a-5p/ESR1, miR-503-5p/CCND1). Finally, our computational analysis predicts that the combination of HNF4α transduction with subsequent AZA treatment might cause changes in hepatic cell proliferation and maturation (miR-18a-5p/ESR1, miR-503-5p/CCND1, miR-328-3p/CD44) as well as the apoptosis (miR-16-5p/BCL2, miR-17-5p/BCL2, miR-34a-5p/BCL2 and miR-494-3p/HMOX1) of naïve rLEC. View Full-Text
Keywords: liver-enriched transcription factor; azacytidine; microRNA; liver progenitor cell; lentiviral transduction; gene expression; rat liver epithelial cells liver-enriched transcription factor; azacytidine; microRNA; liver progenitor cell; lentiviral transduction; gene expression; rat liver epithelial cells
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MDPI and ACS Style

Bolleyn, J.; Rombaut, M.; Nair, N.; Branson, S.; Heymans, A.; Chuah, M.; VandenDriessche, T.; Rogiers, V.; De Kock, J.; Vanhaecke, T. Genetic and Epigenetic Modification of Rat Liver Progenitor Cells via HNF4α Transduction and 5’ Azacytidine Treatment: An Integrated miRNA and mRNA Expression Profile Analysis. Genes 2020, 11, 486. https://doi.org/10.3390/genes11050486

AMA Style

Bolleyn J, Rombaut M, Nair N, Branson S, Heymans A, Chuah M, VandenDriessche T, Rogiers V, De Kock J, Vanhaecke T. Genetic and Epigenetic Modification of Rat Liver Progenitor Cells via HNF4α Transduction and 5’ Azacytidine Treatment: An Integrated miRNA and mRNA Expression Profile Analysis. Genes. 2020; 11(5):486. https://doi.org/10.3390/genes11050486

Chicago/Turabian Style

Bolleyn, Jennifer, Matthias Rombaut, Nisha Nair, Steven Branson, Anja Heymans, Marinee Chuah, Thierry VandenDriessche, Vera Rogiers, Joery De Kock, and Tamara Vanhaecke. 2020. "Genetic and Epigenetic Modification of Rat Liver Progenitor Cells via HNF4α Transduction and 5’ Azacytidine Treatment: An Integrated miRNA and mRNA Expression Profile Analysis" Genes 11, no. 5: 486. https://doi.org/10.3390/genes11050486

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