An Epigenome-Wide Association Study of Inflammatory Response to Fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network

Yusuf, Nabiha; Hidalgo, Bertha; Irvin, Marguerite R.; Jiang, Sha; Zhi, Degui; Tiwari, Hemant K.; Absher, Devin; Arnett, Donna K.; Aslibekyan, Stella

doi:10.2217/pgs-2017-0037

Cited by 9 publications

(7 citation statements)

References 56 publications

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“…Metabolic reprogramming mediated by RPTOR is emerging as essential in T helper cell differentiation [ 25 ]. In previous studies, a different set of CpGs related to RPTOR have been associated with inflammatory markers in CD4T [ 26 ]. Interestingly, SLFN5 (Schlafen factor 5 protein) demethylation strongly delineates monocytes from neutrophils and other cell types.…”

Section: Discussionmentioning

confidence: 99%

An optimized library for reference-based deconvolution of whole-blood biospecimens assayed using the Illumina HumanMethylationEPIC BeadArray

et al. 2018

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Genome-wide methylation arrays are powerful tools for assessing cell composition of complex mixtures. We compare three approaches to select reference libraries for deconvoluting neutrophil, monocyte, B-lymphocyte, natural killer, and CD4+ and CD8+ T-cell fractions based on blood-derived DNA methylation signatures assayed using the Illumina HumanMethylationEPIC array. The IDOL algorithm identifies a library of 450 CpGs, resulting in an average R2 = 99.2 across cell types when applied to EPIC methylation data collected on artificial mixtures constructed from the above cell types. Of the 450 CpGs, 69% are unique to EPIC. This library has the potential to reduce unintended technical differences across array platforms.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1448-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

An optimized library for reference-based deconvolution of whole-blood biospecimens assayed using the Illumina HumanMethylationEPIC BeadArray

et al. 2018

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“…The histone H3 lysine 4 methyltransferase, Mll4/Kmt2d, directs overnutrition-induced murine steatosis via its coactivator function for PPARγ2, whereby overnutrition activates Abl1 kinase which phosphorylates PPARγ2, and hence has enhanced interaction with Mll4 ( Kim et al, 2016 ). DNA methylation status of certain CpGs in CD4 + T cells is associated with the inflammatory response in people undergoing a 3-week fenofibrate treatment in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study ( Yusuf et al, 2017 ). Furthermore, Dnmt1, a maintenance enzyme responsible for de novo methylation, regulates the methylation status of the PPARγ promoter in macrophages, where more Dnmt1 correlates with less PPARγ gene expression levels in atherosclerosis patients’ monocytes ( Yu et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator Activated Receptor Agonists Modulate Transposable Element Expression in Brain and Liver

Ferguson

Zhang

Wang

et al. 2018

Front. Mol. Neurosci.

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Peroxisome proliferator activated receptors (PPARs) are nuclear hormone receptors that act as transcription factors in response to endogenous lipid messengers. The fibrates and thiazolidinediones are synthetic PPAR agonists used clinically to treat dyslipidemia and Type 2 Diabetes Mellitus, respectively, but also improve symptoms of several other diseases. Transposable elements (TEs), repetitive sequences in mammalian genomes, are implicated in many of the same conditions for which PPAR agonists are therapeutic, including neurodegeneration, schizophrenia, and drug addiction. We tested the hypothesis that there is a link between actions of PPAR agonists and TE expression. We developed an innovative application of microarray data by mapping Illumina mouse WG-6 microarray probes to areas of the mouse genome that contain TEs. Using this information, we assessed the effects of systemic administration of three PPAR agonists with different PPAR subtype selectivity: fenofibrate, tesaglitazar, and bezafibrate, on TE probe expression in mouse brain [prefrontal cortex (PFC) and amygdala] and liver. We found that fenofibrate, and bezafibrate to a lesser extent, up-regulated probes mapped to retrotransposons: Short-Interspersed Elements (SINEs) and Long-Interspersed Elements (LINEs), in the PFC. Conversely, all PPAR agonists down-regulated LINEs and tesaglitazar and bezafibrate also down-regulated SINEs in liver. We built gene coexpression networks that partitioned the diverse transcriptional response to PPAR agonists into groups of probes with highly correlated expression patterns (modules). Most of the differentially expressed retrotransposons were within the same module, suggesting coordinated regulation of their expression, possibly by PPAR signaling. One TE module was conserved across tissues and was enriched with genes whose products participate in epigenetic regulation, suggesting that PPAR agonists affect TE expression via epigenetic mechanisms. Other enriched functional categories included phenotypes related to embryonic development and learning and memory, suggesting functional links between these biological processes and TE expression. In summary, these findings suggest mechanistic relationships between retrotransposons and PPAR agonists and provide a basis for future exploration of their functional roles in brain and liver.

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“…Systemic development of those inflammatory markers can be influenced by not only environmental [ 12 , 13 , 14 ] but also genetic and epigenetic factors [ 15 , 16 ]. Despite advances in the understanding of genetic variance and gene–environment (G × E) interactions in relation to those biomarkers, common genetic variants from genome-wide association studies (GWASs) explain a small proportion of inter-individual variability (CRP < 5%; IL-6 < 2%) [ 17 , 18 ], indicating that a large proportion of heritability is undetermined.…”

Section: Introductionmentioning

confidence: 99%

Molecular Biology Networks and Key Gene Regulators for Inflammatory Biomarkers Shared by Breast Cancer Development: Multi-Omics Systems Analysis

et al. 2021

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As key inflammatory biomarkers C-reactive protein (CRP) and interleukin-6 (IL6) play an important role in the pathogenesis of non-inflammatory diseases, including specific cancers, such as breast cancer (BC). Previous genome-wide association studies (GWASs) have neither explained the large proportion of genetic heritability nor provided comprehensive understanding of the underlying regulatory mechanisms. We adopted an integrative genomic network approach by incorporating our previous GWAS data for CRP and IL6 with multi-omics datasets, such as whole-blood expression quantitative loci, molecular biologic pathways, and gene regulatory networks to capture the full range of genetic functionalities associated with CRP/IL6 and tissue-specific key drivers (KDs) in gene subnetworks. We applied another systematic genomics approach for BC development to detect shared gene sets in enriched subnetworks across BC and CRP/IL6. We detected the topmost significant common pathways across CRP/IL6 (e.g., immune regulatory; chemokines and their receptors; interferon γ, JAK-STAT, and ERBB4 signaling), several of which overlapped with BC pathways. Further, in gene–gene interaction networks enriched by those topmost pathways, we identified KDs—both well-established (e.g., JAK1/2/3, STAT3) and novel (e.g., CXCR3, CD3D, CD3G, STAT6)—in a tissue-specific manner, for mechanisms shared in regulating CRP/IL6 and BC risk. Our study may provide robust, comprehensive insights into the mechanisms of CRP/IL6 regulation and highlight potential novel genetic targets as preventive and therapeutic strategies for associated disorders, such as BC.

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An Epigenome-Wide Association Study of Inflammatory Response to Fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network

Cited by 9 publications

References 56 publications

An optimized library for reference-based deconvolution of whole-blood biospecimens assayed using the Illumina HumanMethylationEPIC BeadArray

An optimized library for reference-based deconvolution of whole-blood biospecimens assayed using the Illumina HumanMethylationEPIC BeadArray

Peroxisome Proliferator Activated Receptor Agonists Modulate Transposable Element Expression in Brain and Liver

Molecular Biology Networks and Key Gene Regulators for Inflammatory Biomarkers Shared by Breast Cancer Development: Multi-Omics Systems Analysis

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