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DNA Hypomethylation of a Transcription Zhu et al. Clinical Epigenetics (2017) 9:99 DOI 10.1186/s13148-017-0401-z RESEARCH Open Access DNA hypomethylation of a transcription factor binding site within the promoter of a gout risk gene NRBP1 upregulates its expression by inhibition of TFAP2A binding Zaihua Zhu1,2, Weida Meng3, Peiru Liu3, Xiaoxia Zhu1,2, Yun Liu3* and Hejian Zou1,2* Abstract Background: Genome-wide association studies (GWASs) have identified dozens of loci associated with gout, but for most cases, the risk genes and the underlying molecular mechanisms contributing to these associations are unknown. This study sought to understand the molecular mechanism of a common genetic variant, rs780093, in the development of gout, both in vitro and in vivo. Results: Nuclear receptor binding protein 1 (NRBP1), as a gout risk gene, and its regulatory region, 72 bp upstream of the transcription start site, designated as B1, were identified through integrative analyses of genome-wide genotype and DNA methylation data. We observed elevated NRBP1 expression in human peripheral blood mononuclear cells (PBMCs) from gout patients. In vitro luciferase reporter and protein pulldown assay results showed that DNA methylation could increase the binding of the transcription factor TFAP2A to B1, leading to suppressed gene expression. There results were further confirmed by in vivo bisulfite pyrosequencing showing that hypomethylation on B1 is associated with increased NRBP1 expression in gout patients. Conclusions: Hypomethylation at the promoter region of NRBP1 reduces the binding of TFAP2A and thus leads to elevated NRBP1 expression, which might contribute to the development of gout. Keywords: Gout, Uric acid, DNA methylation, NRBP1, TFAP2A Background longevity and well-being, such as hypertension, diabetes Gout is a complex disorder caused by deposition of mellitus, metabolic syndrome, and renal and cardiovas- monosodium urate (MSU) crystals within joints with a cular disease [4–9]. In particular, gout is increasingly prevalence of 1.14% in adults in China [1]. The male to recognized as an independent cardiovascular risk factor female sex ratio is generally around 3–4 to 1 [2]. Initial [2, 10]. Over the past decade, genome-wide association symptom includes severely painful episodes of peripheral studies (GWASs) and subsequent meta-analyses have led joint synovitis, but it can eventually lead to joint damage to a considerable expansion in the knowledge of com- and deformity, chronic usage-related pain, and subcuta- mon genetic loci that are associated with gout and ele- neous tophus deposition. Central to the development of vated serum urate level [11–15]. However, apart from gout is elevated serum uric acid concentrations [3]. Gout genes coding uric acid transporters, the mechanisms of is also associated with many conditions that affect how most of genetic variances identified from GWAS regulating urate level and developing into gout still re- main poorly understood. As a common human disease, * Correspondence: [email protected]; [email protected] 3The Ministry of Education Key Laboratory of Metabolism and Molecular it is possible that both genetic predisposition and envir- Medicine, Department of Biochemistry and Molecular Biology, School of onmental exposure sharp its risk and contribute to its Basic Medical Sciences, Fudan University, Shanghai, China pathogenesis [16]. 1Division of Rheumatology and Immunology, Huashan Hospital, Fudan University, Shanghai, China Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhu et al. Clinical Epigenetics (2017) 9:99 Page 2 of 9 Epigenetics, such as histone modifications, DNA The inclusion criteria for gout patients are (1) no other methylation, higher chromatin structure, and noncoding diseases except for gout, (2) no treatments in the last RNAs, can be influenced by genetic as well as environ- 3 months, (3) male, (4) age between 18 and 50, and (5) mental factors [17], and thus it can be a potential mech- never smoker. Clinical characteristics of cases and con- anism leading towards gout [18–20]. DNA methylation, trols are shown in Table 1. Additionally, no study sub- an ancient and crucial epigenetic modification, is the jects have ever suffered from cancer. PBMCs from 17 heritable methylation of cytosines in the context of gout patients and 15 matched controls were used for cytosine-guanine dinucleotides (CpGs) without changing measurement of NRBP1 RNA level and methylation of the DNA sequence itself [21]. It is commonly believed B1. PBMCs from an additional set of 7 gout patients that DNA methylation can disrupt the interactions be- and7matchedcontrolswereusedformeasurementof tween transcription factors (TFs) and DNA either directly NRBP1 protein level. [22] or indirectly by recruiting methyl CpG-binding proteins, such as MeCP2, that occupy the methylated Integrative analyses of genotype and DNA methylation promoters and compete for the TF binding sites [22]. Data collection and processing for integrative genotype However, some recent findings show that TFs could and DNA methylation data were performed as described specifically bind to methylated CpG sites with specific previously with minor modifications [17]. Briefly, DNA DNA sequences (DNA motifs) and promote gene ex- methylation data from human blood and genotype data pression in vitro [23]. from the same cohort was obtained from the Gene Expres- In the past decade, it has been shown that DNA methy- sion Omnibus (GEO) with accession number GSE42861. lation may play a role in many human autoimmune dis- Disease-associated SNPs were collected from the NHGRI eases, such as systemic lupus erythematosus, rheumatoid Catalog of Published GWASs [11–15], and a total of 105 arthritis, multiple sclerosis, systemic scleroderma, and SNPs, identified previously to be associated with gout or Sjogren’s syndrome [24]. The identification of dysregula- urate levels, were included for downstream genotype- tion of DNA methylation may inspire the discovery of methylation analyses. Associations between genotype and other uncharacterized mechanisms. Understanding the DNA methylation were evaluated using an additive minor- molecular mechanisms involved in the pathophysiology of allele dosage model and SNP-CpG pairs with a stringent autoimmune diseases is essential for the discovering of Bonferroni-adjusted P value less than 0.05 were deter- diagnostic biomarkers, as well as the introduction of ef- mined to be significant, as suggested previously [17]. fective and target-directed therapies [25]. However, there is no research regarding the role of epigenetics in gout up Quantitative real-time PCR (qPCR) to now. Total cellular RNA of PBMCs was isolated with TRIzol Here, by integrating genotype with DNA methylation, reagent (Invitrogen, Carlsbad, USA). cDNA was gener- we identified a gout risk gene, nuclear receptor binding ated by reverse transcription (PrimeScript RT Reagent protein 1 (NRBP1). We demonstrated that hypomethyla- kit; Takara), and the expression of NRBP1 was quantified tion of its promoter region, 72 bp upstream of NRBP1 by qPCR using LightCycler 480 SYBR Green I Master transcription start site (designated as B1 thereafter), is Mix (Roche) normalized to GAPDH (more details in associated with increased gene expression both in vitro Additional file 2: File 1a). A non-template negative control and in vivo. Moreover, gout-associated increased expres- (water) and a standard curve were conducted for each sion of NRBP1 is regulated through methylation- assay. The efficiency of amplification was determined dependent TFAP2A binding to the B1 region. Table 1 Clinical characteristics of study subjects Methods Characteristic Cases (n = 15) Controls (n = 17) P value Study design Age (years) 39.33 ± 5.94 36.12 ± 7.66 0.12 The study design is shown in Additional file 1: Figure S1. Male (n)15171 Serum uric acid (μmol/L) 535.80 ± 38.31 320.65 ± 66.80 1.42E−11 Clinical samples Creatinine (μmol/L) 68.80 ± 28.18 56.94 ± 12.00 0.21 The study was approved by the Ethics Committees of Body mass index (kg/m2) 24.81 ± 3.64 22.16 ± 3.52 0.04 Huashan Hospital, Fudan University. PBMCs were har- vested from males with gout before any medical treatment Cholesterol (mg/dL) 197.20 ± 99.09 134.24 ± 49.02 0.03 and matched healthy volunteers. Gout patients were diag- Triglycerides (mg/dL) 149.73 ± 33.21 120.29 ± 43.33 0.04 nosed and met the requirements of the 1977 American Cancer (n)001 Rheumatism Association preliminary criteria [26]. Gout Smoker (n)00 1 patients were also with primary hyperuricemia, defined as Values are mean ± SD or numbers. P value for the difference between cases serum uric acid concentrations higher than 7 mg/dL [27]. and controls Zhu et al. Clinical Epigenetics (2017) 9:99 Page 3 of 9 based on the standard curve for mRNA quantification. All subcloned into pCpGL promoter region to generate assays were performed in triplicates, and no obvious pCpGL-8X-B1. Methylation of the luciferase
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