Hepatic lipid accumulation alters global histone h3 lysine 9 and 4 trimethylation in the peroxisome proliferator-activated receptor alpha network - PubMed (original) (raw)

Hepatic lipid accumulation alters global histone h3 lysine 9 and 4 trimethylation in the peroxisome proliferator-activated receptor alpha network

Hee-Jin Jun et al. PLoS One. 2012.

Erratum in

Abstract

Recent data suggest that the etiology of several metabolic diseases is closely associated with transcriptome alteration by aberrant histone methylation. We performed DNA microarray and ChIP-on-chip analyses to examine transcriptome profiling and trimethylation alterations to identify the genomic signature of nonalcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease. Transcriptome analysis showed that steatotic livers in high-fat diet-fed apolipoprotein E2 mice significantly altered the expression of approximately 70% of total genes compared with normal diet-fed control livers, suggesting that hepatic lipid accumulation induces dramatic alterations in gene expression in vivo. Also, pathway analysis suggested that genes encoding chromatin-remodeling enzymes, such as jumonji C-domain-containing histone demethylases that regulate histone H3K9 and H3K4 trimethylation (H3K9me3, H3K4me3), were significantly altered in steatotic livers. Thus, we further investigated the global H3K9me3 and H3K4me3 status in lipid-accumulated mouse primary hepatocytes by ChIP-on-chip analysis. Results showed that hepatic lipid accumulation induced aberrant H3K9me3 and H3K4me3 status in peroxisome proliferator-activated receptor alpha and hepatic lipid catabolism network genes, reducing their mRNA expression compared with non-treated control hepatocytes. This study provides the first evidence that epigenetic regulation by H3K9me3 and H3K4me3 in hepatocytes may be involved in hepatic steatosis and the pathogenesis of NAFLD. Thus, control of H3K9me3 and H3K4me3 represents a potential novel NAFLD prevention and treatment strategy.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Transcriptome profile of the steatotic livers of high-fat diet-fed hAPOE2 mice determined by oligonucleotide microarray analysis.

(A) H&E staining of the livers of normal diet- and high-fat diet-fed hAPOE2 mice (original magnification, ×400). (B) Heat map of the transcriptome profile of the steatotic livers of high-fat diet-fed hAPOE2 mice. Columns represent individual arrays and rows indicate gene expression profiles. Red, blue, and white indicate upregulated, downregulated, and unaltered genes, respectively (p<0.05, n = 6). (C) mRNA expression of genes encoding epigenetic modifiers in the steatotic livers of high-fat diet-fed hAPOE2 mice (p<0.05).

Figure 2

Figure 2. Genome-wide H3K9me3 and H3K4me3 variations in lipid-accumulated mouse primary hepatocytes determined by ChIP-on-chip analysis.

(A) BODIPY-labeled lipid droplets in non- and palmitate plus oleate-treated mouse primary hepatocytes. (B) Expression pattern of H3K9me3 and H3K4me3 targets (fold change ≥1.5 in at least one histone trimethylation status, p<0.05, n = 2 for each histone status, H3K9me3 and H3K4me3) in lipid-accumulated hepatocytes. (C) Biological pathways affected by H3K9me3 and H3K4me3 targets in response to lipid accumulation in hepatocytes (p<0.05).

Figure 3

Figure 3. Effect of H3K4me3 and H3K9me3 on the PPARα-network in lipid-accumulated mouse primary hepatocytes.

Lipid metabolism-associated H3K9me3 and H3K4me3 targets (p<0.05) were selected based on Gene Ontology annotation, and their biological relationship was analyzed using the PubGene database. Red indicates H3K9me3 and H3K4me3 targets detected by ChIP-on-chip analysis and dark red represents those genes possessing a potential biological relationship with targets detected by ChIP-on-chip analysis based on previous reports.

Figure 4

Figure 4. ChIP analysis of mRNA levels of H3K9me3 and H3K4me3 and selected Pparα network genes (n = 3).

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This study was supported by the Technology Development Program for Fisheries of the Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea (iPET, F20926409H220000110), and the Basic Science Research Program of the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (20100028180). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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