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Conference Paper: Epigenetic Regulation of Gene Expression in NAFLD

TitleEpigenetic Regulation of Gene Expression in NAFLD
Authors
Issue Date2012
PublisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastro
Citation
The 2012 Digestive Disease Week (DDW), San Diego, CA., 19-22 May 2012. In Gastroenterology, 2012, v. 142 n. 5 suppl., p. S-929, abstract no. 823 How to Cite?
AbstractBACKGROUND: Epigenetic modifications play an important role in the regulation of gene expression through response to environmental and developmental cues. Gene-environment interactions may impact which patients with nonalcoholic fatty liver disease (NAFLD) develop hepatic injury and progressive fibrosis (advanced NAFLD) rather than simple steatosis (mild NAFLD). The aim of this study was to identify sites of epigenetic regulation that affect liver gene expression patterns in NAFLD. METHODS: RNA and DNA were extracted from liver biopsies of 56 patients with NAFLD (33 mild NAFLD, F0-1; 23 advanced NAFLD, F3-4). Gene expression data were generated using Affymetrix human genome U133 Plus 2.0 arrays and Illumina Infinium HumanMethylation450 BeadChips were used to profile DNA methylation of >485,000 CpG dinucleotides (CpGs) from the same biopsy specimens. Methylation intensity was assessed via log2 ratio of methylated to unmethylated bead intensities. Differentially methylated CpGs were identified using an ANOVA model, adjusting for age and gender. After correcting for multiple comparisons, a q-value of<0.05 was considered significant. Differentially methylated CpGs inversely related with gene expression (r<-0.3; p-value<0.02) were determined. Generalized topological overlapping measure (GTOM) analysis was used to identify groups of genes showing coordinate epigenetic regulation, referred to as modules. RESULTS: There were 1143 genes with significant differential expression and 76,833 CpGs with differential methylation in mild vs. advanced NAFLD. Among these, 4,849 CpGs were negatively correlated with gene expression indicating a potential regulatory relationship between methylation status and transcription. GTOM analysis grouped the genes into 10 modules relating those with similar biologic function. Relative to mild NAFLD, 705 genes (22.2%) were hypermethylated and down-regulated (hyperM/down) in advanced NAFLD while 885 (27.9%) were hypomethylated and up-regulated (hypoM/up). Ingenuity Pathway Analysis revealed modules with hyperM/down genes to be involved in PXR/RXR activation (CYP1A2, CYP2C19, NR1I2, RXRA ) and metabolic processes (ADH6, DGAT2, MAT1A, OAT, PPP1R3B) while modules with hypoM/up genes are involved in cell signaling, matrix remodeling (CD44,COL1A1, ITGB2) and T cell immune responses (IL12R, NFKB STAT1). Further analysis revealed social alcohol, coffee and statin consumption was associated with methylation patterns in advanced NAFLD similar to those of non-consumers with mild NAFLD. CONCLUSIONS: We report the first genome-wide methylation study in patients with NAFLD. Integrated analysis of gene expression and methylation data obtained using high-throughout technologies is valuable for identification of relevant molecular events involved in advanced NAFLD and may reveal potential diagnostic and therapeutic biomarkers.
DescriptionThis journal suppl. entitled: 2012 DDW Abstract Supplement to Gastroenterology
Persistent Identifierhttp://hdl.handle.net/10722/195770
ISSN
2015 Impact Factor: 18.187
2015 SCImago Journal Rankings: 7.170

 

DC FieldValueLanguage
dc.contributor.authorMoylan, CAen_US
dc.contributor.authorYang, Hen_US
dc.contributor.authorPang, HMHen_US
dc.contributor.authorDellinger, Aen_US
dc.contributor.authorSuzuki, Aen_US
dc.contributor.authorTillmann, HLen_US
dc.contributor.authorGuy, CDen_US
dc.contributor.authorAshley-Koch, AEen_US
dc.contributor.authorGarrett, MEen_US
dc.contributor.authorAbdelmalek, MFen_US
dc.date.accessioned2014-03-10T04:52:54Z-
dc.date.available2014-03-10T04:52:54Z-
dc.date.issued2012en_US
dc.identifier.citationThe 2012 Digestive Disease Week (DDW), San Diego, CA., 19-22 May 2012. In Gastroenterology, 2012, v. 142 n. 5 suppl., p. S-929, abstract no. 823en_US
dc.identifier.issn0016-5085en_US
dc.identifier.urihttp://hdl.handle.net/10722/195770-
dc.descriptionThis journal suppl. entitled: 2012 DDW Abstract Supplement to Gastroenterology-
dc.description.abstractBACKGROUND: Epigenetic modifications play an important role in the regulation of gene expression through response to environmental and developmental cues. Gene-environment interactions may impact which patients with nonalcoholic fatty liver disease (NAFLD) develop hepatic injury and progressive fibrosis (advanced NAFLD) rather than simple steatosis (mild NAFLD). The aim of this study was to identify sites of epigenetic regulation that affect liver gene expression patterns in NAFLD. METHODS: RNA and DNA were extracted from liver biopsies of 56 patients with NAFLD (33 mild NAFLD, F0-1; 23 advanced NAFLD, F3-4). Gene expression data were generated using Affymetrix human genome U133 Plus 2.0 arrays and Illumina Infinium HumanMethylation450 BeadChips were used to profile DNA methylation of >485,000 CpG dinucleotides (CpGs) from the same biopsy specimens. Methylation intensity was assessed via log2 ratio of methylated to unmethylated bead intensities. Differentially methylated CpGs were identified using an ANOVA model, adjusting for age and gender. After correcting for multiple comparisons, a q-value of<0.05 was considered significant. Differentially methylated CpGs inversely related with gene expression (r<-0.3; p-value<0.02) were determined. Generalized topological overlapping measure (GTOM) analysis was used to identify groups of genes showing coordinate epigenetic regulation, referred to as modules. RESULTS: There were 1143 genes with significant differential expression and 76,833 CpGs with differential methylation in mild vs. advanced NAFLD. Among these, 4,849 CpGs were negatively correlated with gene expression indicating a potential regulatory relationship between methylation status and transcription. GTOM analysis grouped the genes into 10 modules relating those with similar biologic function. Relative to mild NAFLD, 705 genes (22.2%) were hypermethylated and down-regulated (hyperM/down) in advanced NAFLD while 885 (27.9%) were hypomethylated and up-regulated (hypoM/up). Ingenuity Pathway Analysis revealed modules with hyperM/down genes to be involved in PXR/RXR activation (CYP1A2, CYP2C19, NR1I2, RXRA ) and metabolic processes (ADH6, DGAT2, MAT1A, OAT, PPP1R3B) while modules with hypoM/up genes are involved in cell signaling, matrix remodeling (CD44,COL1A1, ITGB2) and T cell immune responses (IL12R, NFKB STAT1). Further analysis revealed social alcohol, coffee and statin consumption was associated with methylation patterns in advanced NAFLD similar to those of non-consumers with mild NAFLD. CONCLUSIONS: We report the first genome-wide methylation study in patients with NAFLD. Integrated analysis of gene expression and methylation data obtained using high-throughout technologies is valuable for identification of relevant molecular events involved in advanced NAFLD and may reveal potential diagnostic and therapeutic biomarkers.-
dc.languageengen_US
dc.publisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastroen_US
dc.relation.ispartofGastroenterologyen_US
dc.titleEpigenetic Regulation of Gene Expression in NAFLDen_US
dc.typeConference_Paperen_US
dc.identifier.emailPang, HMH: herbpang@hku.hken_US
dc.identifier.authorityPang, HMH=rp01857en_US
dc.identifier.doi10.1016/S0016-5085(12)63603-8-
dc.identifier.volume142en_US
dc.identifier.issue5 suppl.-
dc.identifier.spageS-929, abstract no. 823en_US
dc.identifier.epageS-929, abstract no. 823en_US
dc.publisher.placeUnited Statesen_US

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