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Altered Intragenic DNA Methylation of HOOK2 Gene in Adipose Tissue from Individuals with Obesity and Type 2 Diabetes

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Altered Intragenic DNA Methylation of HOOK2 Gene in Adipose Tissue from Individuals with Obesity and Type 2 Diabetes RESEARCH ARTICLE Altered intragenic DNA methylation of HOOK2 gene in adipose tissue from individuals with obesity and type 2 diabetes Sandra RodrõÂguez-Rodero1,2,3☯, Edelmiro MeneÂndez-Torre1,3☯, Gustavo FernaÂndez- Bayo n2,3, Paula Morales-SaÂnchez1,2,3, Lourdes Sanz4, Estrella Turienzo4, Juan Jose GonzaÂlez4, Ceferino Martinez-Faedo1,3, Lorena Suarez-GutieÂrrez1,3, Jessica Ares1,3, Lucia DõÂaz-Naya1,3, Alicia Martin-Nieto1,3, Juan L. FernaÂndez-Morera1,3, Mario F. Fraga3,5³, ElõÂas Delgado-A lvarez1,3,6³* a1111111111 a1111111111 1 Endocrinology and Nutrition Department, Hospital Universitario Central de Asturias (HUCA), Asturias, a1111111111 Spain, 2 Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de a1111111111 Oviedo, Asturias, Spain, 3 Endocrinology, Nutrition, Diabetes and Obesity Unit, Instituto de InvestigacioÂn a1111111111 Sanitaria del Principado de Asturias (ISPA), Oviedo, Asturias, Spain, 4 Surgery Department, Hospital Universitario Central de Asturias, Asturias, Spain, 5 Centro de InvestigacioÂn en Nanomateriales y NanotecnologõÂa (CINN), El Entrego, Asturias, Spain, 6 Medicine Department, Universidad de Oviedo, Asturias, Spain ☯ These authors contributed equally to this work. OPEN ACCESS ³ These authors also contributed equally to this work. * [email protected], [email protected] Citation: RodrõÂguez-Rodero S, MeneÂndez-Torre E, FernaÂndez-BayoÂn G, Morales-SaÂnchez P, Sanz L, Turienzo E, et al. (2017) Altered intragenic DNA methylation of HOOK2 gene in adipose tissue from Abstract individuals with obesity and type 2 diabetes. PLoS ONE 12(12): e0189153. https://doi.org/10.1371/ journal.pone.0189153 Aims/Hypothesis Editor: Jorg Tost, Institut de genomique, FRANCE Failure in glucose response to insulin is a common pathology associated with obesity. In this Received: May 25, 2017 study, we analyzed the genome wide DNA methylation profile of visceral adipose tissue Accepted: November 20, 2017 (VAT) samples in a population of individuals with obesity and assessed whether differential methylation profiles are associated with the presence of type 2 diabetes (T2D). Published: December 11, 2017 Copyright: © 2017 RodrõÂguez-Rodero et al. This is Methods an open access article distributed under the terms of the Creative Commons Attribution License, More than 485,000 CpG genome sites from VAT samples from women with obesity under- which permits unrestricted use, distribution, and going gastric bypass (n = 18), and classified as suffering from type 2 diabetes (T2D) or not reproduction in any medium, provided the original (no type 2 diabetes, NT2D), were analyzed using DNA methylation arrays. author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information Results files. We found significant differential methylation between T2D and NT2D samples in 24 CpGs Funding: This work was supported by grants from that map with sixteen genes, one of which, HOOK2, demonstrated a significant correlation the FundacioÂn Mutua Madrileña (IX Convocatoria between differentially hypermethylated regions on the gene body and the presence of type 2 de Ayudas para la InvestigacioÂn ClõÂnica-2012), diabetes. This was validated by pyrosequencing in a population of 91 samples from both Instituto de Salud Carlos III (FIS PI11/02795 and FIS P14/00970) and the Sociedad Española de males and females with obesity. Furthermore, when these results were analyzed by gender, Diabetes (SED) (in 2012). female T2D samples were found hypermethylated at the cg04657146-region and the cg Competing interests: The authors have declared 11738485-region of HOOK2 gene, whilst, interestingly, male samples were found hypo- that no competing interests exist. methylated in this latter region. PLOS ONE | https://doi.org/10.1371/journal.pone.0189153 December 11, 2017 1 / 15 Altered HOOK2 methylation in women with T2D Conclusion The differential methylation profile of the HOOK2 gene in individuals with T2D and obesity might be related to the attendant T2D, but further studies are required to identify the poten- tial role of HOOK2 gene in T2D disease. The finding of gender differences in T2D methyla- tion of HOOK2 also warrants further investigation. Introduction Obesity is frequently associated with the resistance of peripheral tissues (muscle and adipose) to the action of insulin. Because of a state of inflammation in adipose tissue infiltrated by inflammatory cells, secretions from these cells and fat derived adipokines promote the devel- opment of type 2 diabetes (T2D) [1±3]. Genome wide studies have led to the characterization of gene variants that are associated with an increased risk of T2D development, but their effect size is reduced when compared with traditional risk factors such as obesity, unhealthy diet or family history of diabetes [4]. Previous works have demonstrated alterations in methylation profiles of genes involved in the pathogenesis of obesity and T2D development [5]. For example, in subcutaneous adipose tissue from a group of 31 healthy men following exposure to exercise training [6], changes in methylation were found related to variations in mRNA expression in some of the T2D associ- ated genes±±HHEX (Hematopoietically-Expressed Homeobox Protein), IGF2BP2 (Insulin-like Growth Factor 2 Binding Protein 2), JAZF1 (JAZF Zinc Finger 1) and TCF7L2 (Transcription Factor 7-like 2). Ribel-Madsen et al conducted genome-wide methylation studies in insulin responsive tissues (skeletal muscle and subcutaneous adipose tissue) in elderly monozygotic (MZ) twin pairs discordant for T2D [7]. Methylation differences were found on the promoter region of CDKN2A (Cyclin-Dependent Kinase Inhibitor 2A) and HNF4A (Hepatocyte Nuclear Factor 4 Alpha) genes, although greater differences were found in genome wide repetitive DNA sequences such as LINE-1. These results were complemented by Nilsson et al, who described 1410 differentially methylated CpG sites between MZ T2D discordant twins, including KCNQ1 (Potassium Channel Voltage Gated KQT-like Subfamily Q, Member 1), NOTCH2 (Neurogenic Locus Notch Homolog Protein 2), TCF7L2 (Transcription Factor 7-like 2) and THADA (Thy- roid Adenoma Associated) T2D related genes [8]. Recently, work by Chen et al has demon- strated that promoter hypermethylation of NR4A1 (Nuclear Receptor Subfamily 4 Group A Member 1) was elevated in T2D human samples as well as in T2D murine models and that this hypermethylation was associated with a decrease in mRNA levels. They also found that lack of NR4A1 (Nuclear Receptor Subfamily 4 Group A Member 1) protein is related to an increment in DNMT1 expression and the blocking of insulin signaling in patients with T2D [9]. These results were supported by the genome-wide DNA methylation analysis undertaken by Volkov et al in subcutaneous adipose tissue samples [10], whose work demonstrated an association between genetic and epigenetic mechanisms in terms of an observed relationship between single nucleotide polymorphisms and methylation at CpG sites of genes involved in metabolic pat- terns associated with diabetes development. The majority of T2D cases occur in the context of a metabolic syndrome leading to a chronic excess of energetic substrates and ectopic fat storage, insulin resistance, elevated levels of inflammatory cytokines and, ultimately, a decrease in insulin secretion and the apoptosis of pancreatic β cells. The studies referred to earlier, have demonstrated the DNA methylation of T2D susceptible genes in different tissues (blood, skeletal muscle and fat) which are frequently PLOS ONE | https://doi.org/10.1371/journal.pone.0189153 December 11, 2017 2 / 15 Altered HOOK2 methylation in women with T2D associated with T2D development. Most of these works were carried out on subcutaneous fat, although VAT, along with skeletal muscle and liver, is in fact the most suitable candidate for determining the involvement of gene methylation in T2D development. Visceral fat not only acts as an energy storage tissue, but also as an endocrine organ, which releases hormones and adipokines, that contribute to expand macrophage population in VAT, which also liberate inflammatory cytokines. As the fat depot increases, levels of these molecules also rise and since they modulate the action of insulin in muscle and liver insulin insensitivity may result. VAT tissue has high levels of lipogenesis and lipolysis activity. This can result in hyperlipidemia and glucose intolerance [11]. Moreover, excess free fatty acids lead to ectopic lipid accumulation and lipotoxicity in muscle, where they inhibit glucose uptake, causing insulin resistance in these tissues [12, 13] Prior research has described genome-wide DNA methylation patterns and site-specific dif- ferences in CpG methylation of candidate genes associated with T2D in VAT [14±18]. The aim of the present study is to contribute to the description of the VAT methylome in humans, and to explore the impact of epigenetics in diabetes development. Materials and methods Ethics statement The study protocol (nÊ 68/10) was approved by the Ethical Committee at the Hospital Univer- sitario Central de Asturias (Asturias, Spain) and all participants provided written and oral informed consent. The study was conducted in accordance with the principles of the Helsinki Declaration for human research. Human tissue samples Discovery cohort: a cohort of 18 (8 T2D and 10 NT2D) visceral adipose tissue (VAT) samples was obtained from patients (all female) from the Surgery
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