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Control of gene expression by the Retinoic acid-related Orphan Receptor alpha in HepG2 human hepatoma cells

ABSTRACT: Retinoic acid-related Orphan Receptor alpha (RORalpha; NR1F1) is a nuclear receptor involved in several physiological and patho-physiological functions including lipid metabolism, inflammation, angiogenesis, and circadian rythm. It is widely distributed. In order to better understand the role of this nuclear receptor in liver, we aimed at displaying genes controlled by RORalpha in liver cells. HepG2 human hepatoma cells stably over-expressing RORalpha were designed. Genes whose expression was altered in these cells versus control cells were displayed using micro-arrays and qRT-PCR. Expression of these genes was also altered in cells in which RORalpha was transiently over-expressed after adenoviral infection. Some genes are involved in functions controlled by RORalpha. This is the case for LPA, NR1D2 and ADIPOQ in lipid metabolism, ADIPOQ and PLG in inflammation, PLG in fibrinolysis and NR1D2 and NR1D1 in circadian rhythm. This study also revealed that genes such as G6PC, involved in glucose homeostasis, and AGRP, involved in the control of body weight, are also controlled by RORalpha. Lastly, SPARC, involved in cell growth and adhesion and associated with liver carcinogenesis, was up-regulated by RORalpha. It is a new direct RORalpha target gene since it possesses, in its promoter, a functional RORE as evidenced by EMSAs and transfection experiments. It is likely the case for most of the other genes we found regulated by RORalpha contain putative ROREs in their regulatory regions. These results open new routes to think about the role of RORalpha in glucose metabolism and carcinogenesis within cells of hepatic origin. Keywords: Comparison of HepG2 cells expressing RORalpha or control HepG2 cells cultured in 20% oxygen or 2% oxygen during 24h.

ORGANISM(S): Homo sapiens

PROVIDER: GSE18875 | GEO | 2009/11/04

SECONDARY ACCESSION(S): PRJNA121131

REPOSITORIES: GEO

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Project description:Expression profiling the response to inhibition of DNA methylation and histone deacetylation. Comparison of expression in HepG2 cells treated with 5-aza-dC, Trichostatin A, both, or none (control) to change methylation and acetylation status. Backgroubd: DNA methylation and histone deacetylation are epigenetic mechanisms that play major roles in eukaryotic gene regulation. We hypothesize that many genes in the human hepatoma cell line HepG2 are regulated by DNA methylation and histone deacetylation. Treatment with 5-aza-2'-deoxycytidine (5-aza-dC) to inhibit DNA methylation with and/or Trichostatin A (TSA) to inhibit histone deacetylation should allow us to identify genes that are regulated epigenetically in hepatoma cells. RESULTS: 5-aza-dC had a much larger effect on gene expression in HepG2 cells than did TSA, as measured using Affymetrix HG-U133 Plus 2.0 microarrays. The expression of 1504 probe sets was affected by 5-aza-dC (at p < 0.01), 535 probe sets by TSA, and 1929 probe sets by the combination of 5-aza-dC and TSA. 5-aza-dC treatment turned on the expression of 211 probe sets that were not detectably expressed in its absence. Expression of imprinted genes regulated by DNA methylation, such as H19 and NNAT, was turned on or greatly increased in response to 5-aza-dC. Genes involved in liver processes such as xenobiotic metabolism (CYP3A4, CYP3A5, and CYP3A7) and steroid biosynthesis (CYP17A1 and CYP19A1), and genes encoding CCAAT element-binding proteins (C/EBPalpha, C/EBPbeta, and C/EBPgamma) were affected by 5-aza-dC or the combination. Many of the genes that fall within these groups are also expressed in the developing fetal liver and adult liver. Quantitative real-time RT-PCR assays confirmed selected gene expression changes seen in microarray analyses. CONCLUSION: Epigenetics play a role in regulating the expression of several genes involved in essential liver processes such as xenobiotic metabolism and steroid biosynthesis in HepG2 cells. Many genes whose expression is normally silenced in these hepatoma cells were re-expressed by 5-aza-dC treatment. DNA methylation may be a factor in restricting the expression of fetal genes during liver development and in shutting down expression in hepatoma cells

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Control of gene expression by the Retinoic acid-related Orphan Receptor alpha in HepG2 human hepatoma cells

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