DNA methylation and gene expression of HIF3A: cross-tissue validation and associations with BMI and insulin resistance

Background:Cardiovascular risk factors are increased in Psoriatic Arthritis (PsA). In fact, around 60% out of PsA patients display insulin resistance (IR), a hallmark of metabolic syndrome, which might significantly contribute to the cardiovascular disease. Latest studies suggested that inflammatory and metabolic disorders may be under epigenetic control, including DNA methylation. DNA methylation is an unexplored area in the field of PsA.Objectives:To study the alterations in the genome-wide DNA methylation profile of CD4+T cells from PsA patients and its relationship with its pathology and the risk of cardiovascular comorbidity.Methods:Twenty healthy controls (HC) and 20 PsA patients were included in the study. PsA patients were classified into insulin resistant and non-insulin resistant according to HOMA-IR index. CD4+T lymphocytes were isolated from peripheral blood by positive immunomagnetic selection. The Illumina Infinium MethylationEPIC Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpGs (TSS1500, TSS200, 5UTR, 3UTR, first exon, gene body). Beta values (β) estimating methylation levels were obtained at each CpG site, and differentially methylated genes (DMG) between PsA and HC were identified. Functional classification of these genes was carried out through gene ontology analysis (PANTHER database). Gene expression analysis of the selected genes was also evaluated by RT-PCR. Vascular parameters including carotid intima-media thickness (cIMT) and endothelial function was analyzed by ecodoppler and periflux respectively.Results:The genome-wide methylation analysis identified 112 DMGs including 41 hypomethylated and 71 hypermethylated. These differentially methylated genes were enriched with several signaling pathways and disease categories including immune response, metabolic processes, oxidative stress, vascular and inflammatory pathways. The altered gene expression of selected genes with altered methylation levels in PsA was also validated. Correlation and association analysis of these DMGs with clinical and analytical variables, cardiovascular risk factors and endothelial microvascular function revealed that the degree of methylation of these genes was significantly associated with cIMT (IGF1R, NDRG3, SMYD3, HLA-DRB1, WDR70), arterial pressure (METT5D1, NRDG3, ADAM17, SMYD3, WNK1, CBX1), insulin resistance (AKAP13, SEMA6D, PLCB1), altered lipid profile and atherogenic index (MYBL1, METT5D1, MAN2A1, SLC1A7, SEMA6D, PLCB1, TLK1, SDK1, CBX1), inflammation (MYBL1, NDUFA5, METT5D1, SEMA6D, PLCB1, TLK1), and endothelial dysfunction (ADAMST10, GPCPD1, CCDC88A). In addition, this analysis also identified 435 DMGs including 280 hypomethylated and 155 hypermethylated in CD4+T cells from IR-PsA vs non IR-PsA patients. Between these two groups of PsA patients, CHUK, SERINC1, RUNX1, TTYH2, TXNDC11, FAF1, BICD1, SCD5, PDE5A, FAS, NFIA and GRP75 displayed the most significantly altered methylation, suggesting the role of these genes in the metabolic complications associated with PsA.Conclusion:These findings help our understanding of the pathogenesis of PsA and advance epigenetic studies in regards to this disease and the cardiometabolic comorbidities associated. Funded by ISCIII (PI17/01316 and RIER RD16/0012/0015) co-funded with FEDER.Disclosure of Interests:Iván Arias de la Rosa: None declared, María Dolores López Montilla Speakers bureau: Celgene, Javier Rodríguez: None declared, Esteban Ballester: None declared, Carmen Torres-Granados: None declared, Carlos Perez-Sanchez: None declared, Maria del Carmen Abalos-Aguilera: None declared, Gómez García Ignacio: None declared, Desiree Ruiz: None declared, Alejandra M. Patiño-Trives: None declared, María Luque-Tévar: None declared, Eduardo Collantes-Estévez Grant/research support from: ROCHE and Pfizer., Speakers bureau: ROCHE, Lilly, Bristol and Celgene., Chary Lopez-Pedrera Grant/research support from: ROCHE and Pfizer., Alejandro Escudero Contreras Grant/research support from: ROCHE and Pfizer, Speakers bureau: ROCHE, Lilly, Bristol and Celgene., Nuria Barbarroja Puerto Grant/research support from: ROCHE and Pfizer., Speakers bureau: ROCHE and Celgene.

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Integrative analysis of glucometabolic traits, adipose tissue DNA methylation and gene expression identifies epigenetic regulatory mechanisms of insulin resistance and obesity in African Americans

10.2337/figshare.12896636.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Neeraj K. Sharma ◽

Mary E. Comeau ◽

Dennis Montoya ◽

Matteo Pellegrini ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Dna Methylation ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

African Americans ◽

Association Studies ◽

Regulation Of Gene Expression ◽

Transcript Level ◽

Matsuda Index

Decline in insulin sensitivity due to dysfunction of adipose tissue (AT) is one of the earliest pathogenic events in Type 2 Diabetes. We hypothesize that differential DNA methylation (DNAm) controls insulin sensitivity and obesity by modulating transcript expression in AT. Integrating AT DNAm profiles with transcript profile data measured in a cohort of 230 African Americans from AAGMEx cohort, we performed cis-expression quantitative trait methylation (cis-eQTM) analysis to identify epigenetic regulatory loci for glucometabolic trait-associated transcripts. We identified significantly associated CpG-regions for 82 transcripts (FDR-P<0.05). The strongest eQTM locus was observed for the proopiomelanocortin (POMC; r= -0.632, P= 4.70X10-27) gene. Epigenome-wide association studies (EWAS) further identified 155, 46, and 168 CpG regions associated (FDR-P <0.05) with Matsuda index, SI and BMI, respectively. Intersection of EWAS, transcript level to trait association, and eQTM results, followed by causal inference test identified significant eQTM loci for 23 genes that were also associated with Matsuda index, SI and/or BMI in EWAS. These associated genes include FERMT3, ITGAM, ITGAX, and POMC. In summary, applying an integrative multi-omics approach, our study provides evidence for DNAm-mediated regulation of gene expression at both previously identified and novel loci for many key AT transcripts influencing insulin resistance and obesity.

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MP254VDR GENE EXPRESSION AND GLOBAL DNA METHYLATION ARE ASSOCIATED WITH INSULIN RESISTANCE IN ESRD PATIENTS ON CHRONIC HAEMODIALYSIS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfw188.10 ◽

2016 ◽

Vol 31 (suppl_1) ◽

pp. i424-i425

Author(s):

Dimitrios Kirmizis ◽

Fani Chatzopoulou ◽

Dimitrios Chatzidimitriou ◽

Georgios Tzimagiorgis ◽

Aikaterini Papagianni ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Dna Methylation ◽

Global Dna Methylation ◽

Chronic Haemodialysis ◽

Esrd Patients

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Deoxyribonucleic Acid Methylation and Gene Expression of PPARGC1A in Human Muscle Is Influenced by High-Fat Overfeeding in a Birth-Weight-Dependent Manner

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-2413 ◽

2010 ◽

Vol 95 (6) ◽

pp. 3048-3056 ◽

Cited By ~ 134

Author(s):

Charlotte Brøns ◽

Stine Jacobsen ◽

Emma Nilsson ◽

Tina Rönn ◽

Christine B. Jensen ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Dna Methylation ◽

Birth Weight ◽

Control Diet ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

High Fat ◽

Peroxisome Proliferator Activated Receptor ◽

Peripheral Insulin Resistance

Abstract Context: Low birth weight (LBW) and unhealthy diets are risk factors of metabolic disease including type 2 diabetes (T2D). Genetic, nongenetic, and epigenetic data propose a role of the key metabolic regulator peroxisome proliferator-activated receptor γ, coactivator 1α (PPARGC1A) in the development of T2D. Objective: Our objective was to investigate gene expression and DNA methylation of PPARGC1A and coregulated oxidative phosphorylation (OXPHOS) genes in LBW and normal birth weight (NBW) subjects during control and high-fat diets. Design, Subjects, and Main Outcome Measures: Twenty young healthy men with LBW and 26 matched NBW controls were studied after 5 d high-fat overfeeding (+50% calories) and after a control diet in a randomized manner. Hyperinsulinemic-euglycemic clamps were performed and skeletal muscle biopsies excised. DNA methylation and gene expression were measured using bisulfite sequencing and quantitative real-time PCR, respectively. Results: When challenged with high-fat overfeeding, LBW subjects developed peripheral insulin resistance and reduced PPARGC1A and OXPHOS (P < 0.05) gene expression. PPARGC1A methylation was significantly higher in LBW subjects (P = 0.0002) during the control diet. However, PPARGC1A methylation increased in only NBW subjects after overfeeding in a reversible manner. DNA methylation of PPARGC1A did not correlate with mRNA expression. Conclusions: LBW subjects developed peripheral insulin resistance and decreased gene expression of PPARGC1A and OXPHOS genes when challenged with fat overfeeding. The extent to which our finding of a constitutively increased DNA methylation in the PPARGC1A promoter in LBW subjects may contribute needs to be determined. We provide the first experimental support in humans that DNA methylation induced by overfeeding is reversible.

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Integrative Analysis of Glucometabolic Traits, Adipose Tissue DNA Methylation, and Gene Expression Identifies Epigenetic Regulatory Mechanisms of Insulin Resistance and Obesity in African Americans

Diabetes ◽

10.2337/db20-0117 ◽

2020 ◽

Vol 69 (12) ◽

pp. 2779-2793

Author(s):

Neeraj K. Sharma ◽

Mary E. Comeau ◽

Dennis Montoya ◽

Matteo Pellegrini ◽

Timothy D. Howard ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Dna Methylation ◽

Adipose Tissue ◽

African Americans ◽

Integrative Analysis ◽

Regulatory Mechanisms

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Integrative analysis of glucometabolic traits, adipose tissue DNA methylation and gene expression identifies epigenetic regulatory mechanisms of insulin resistance and obesity in African Americans

10.2337/figshare.12896636 ◽

2020 ◽

Author(s):

Ada Admin ◽

Neeraj K. Sharma ◽

Mary E. Comeau ◽

Dennis Montoya ◽

Matteo Pellegrini ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Dna Methylation ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

African Americans ◽

Association Studies ◽

Regulation Of Gene Expression ◽

Transcript Level ◽

Matsuda Index

Decline in insulin sensitivity due to dysfunction of adipose tissue (AT) is one of the earliest pathogenic events in Type 2 Diabetes. We hypothesize that differential DNA methylation (DNAm) controls insulin sensitivity and obesity by modulating transcript expression in AT. Integrating AT DNAm profiles with transcript profile data measured in a cohort of 230 African Americans from AAGMEx cohort, we performed cis-expression quantitative trait methylation (cis-eQTM) analysis to identify epigenetic regulatory loci for glucometabolic trait-associated transcripts. We identified significantly associated CpG-regions for 82 transcripts (FDR-P<0.05). The strongest eQTM locus was observed for the proopiomelanocortin (POMC; r= -0.632, P= 4.70X10-27) gene. Epigenome-wide association studies (EWAS) further identified 155, 46, and 168 CpG regions associated (FDR-P <0.05) with Matsuda index, SI and BMI, respectively. Intersection of EWAS, transcript level to trait association, and eQTM results, followed by causal inference test identified significant eQTM loci for 23 genes that were also associated with Matsuda index, SI and/or BMI in EWAS. These associated genes include FERMT3, ITGAM, ITGAX, and POMC. In summary, applying an integrative multi-omics approach, our study provides evidence for DNAm-mediated regulation of gene expression at both previously identified and novel loci for many key AT transcripts influencing insulin resistance and obesity.

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Transcriptional and Epigenetic Changes Influencing Skeletal Muscle Metabolism in Women With Polycystic Ovary Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2018-00935 ◽

2018 ◽

Vol 103 (12) ◽

pp. 4465-4477 ◽

Cited By ~ 18

Author(s):

Emma Nilsson ◽

Anna Benrick ◽

Milana Kokosar ◽

Anna Krook ◽

Eva Lindgren ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Dna Methylation ◽

Polycystic Ovary Syndrome ◽

Mrna Expression ◽

Polycystic Ovary ◽

Differentially Expressed ◽

Ovary Syndrome ◽

Cpg Sites

Abstract Context Insulin resistance in skeletal muscle is a major risk factor for the development of type 2 diabetes in women with polycystic ovary syndrome (PCOS). Despite this, the mechanisms underlying insulin resistance in PCOS are largely unknown. Objective To investigate the genome-wide DNA methylation and gene expression patterns in skeletal muscle from women with PCOS and controls and relate them to phenotypic variations. Design/Participants In a case-control study, skeletal muscle biopsies from women with PCOS (n = 17) and age-, weight-, and body mass index‒matched controls (n = 14) were analyzed by array-based DNA methylation and mRNA expression profiling. Results Eighty-five unique transcripts were differentially expressed in muscle from women with PCOS vs controls, including DYRK1A, SYNPO2, SCP2, and NAMPT. Furthermore, women with PCOS had reduced expression of genes involved in immune system pathways. Two CpG sites showed differential DNA methylation after correction for multiple testing. However, an mRNA expression of ∼30% of the differentially expressed genes correlated with DNA methylation levels of CpG sites in or near the gene. Functional follow-up studies demonstrated that KLF10 is under transcriptional control of insulin, where insulin promotes glycogen accumulation in myotubes of human muscle cells. Testosterone downregulates the expression levels of COL1A1 and MAP2K6. Conclusion PCOS is associated with aberrant skeletal muscle gene expression with dysregulated pathways. Furthermore, we identified specific changes in muscle DNA methylation that may affect gene expression. This study showed that women with PCOS have epigenetic and transcriptional changes in skeletal muscle that, in part, can explain the metabolic abnormalities seen in these women.

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