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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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          Abstract

          Aims/Hypothesis

          Failure in glucose response to insulin is a common pathology associated with obesity. In this study, we analyzed the genome wide DNA methylation profile of visceral adipose tissue (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).

          Methods

          More than 485,000 CpG genome sites from VAT samples from women with obesity undergoing gastric bypass (n = 18), and classified as suffering from type 2 diabetes (T2D) or not (no type 2 diabetes, NT2D), were analyzed using DNA methylation arrays.

          Results

          We found significant differential methylation between T2D and NT2D samples in 24 CpGs that map with sixteen genes, one of which, HOOK2, demonstrated a significant correlation between differentially hypermethylated regions on the gene body and the presence of type 2 diabetes. This was validated by pyrosequencing in a population of 91 samples from both males and females with obesity. Furthermore, when these results were analyzed by gender, female T2D samples were found hypermethylated at the cg04657146-region and the cg 11738485-region of HOOK2 gene, whilst, interestingly, male samples were found hypomethylated in this latter region.

          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 potential role of HOOK2 gene in T2D disease. The finding of gender differences in T2D methylation of HOOK2 also warrants further investigation.

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          Most cited references39

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          Cytosine methylation and the ecology of intragenomic parasites.

          Most of the 5-methylcytosine in mammalian DNA resides in transposons, which are specialized intragenomic parasites that represent at least 35% of the genome. Transposon promoters are inactive when methylated and, over time, C-->T transition mutations at methylated sites destroy many transposons. Apart from that subset of genes subject to X inactivation and genomic imprinting, no cellular gene in a non-expressing tissue has been proven to be methylated in a pattern that prevents transcription. It has become increasingly difficult to hold that reversible promoter methylation is commonly involved in developmental gene control; instead, suppression of parasitic sequence elements appears to be the primary function of cytosine methylation, with crucial secondary roles in allele-specific gene expression as seen in X inactivation and genomic imprinting.
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            Genomics, type 2 diabetes, and obesity.

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              Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome.

              DNA methylation is the most studied epigenetic mark and CpG methylation is central to many biological processes and human diseases. Since cancer has highlighted the contribution to disease of aberrant DNA methylation patterns, such as the presence of promoter CpG island hypermethylation-associated silencing of tumor suppressor genes and global DNA hypomethylation defects, their importance will surely become apparent in other pathologies. However, advances in obtaining comprehensive DNA methylomes are hampered by the high cost and time-consuming aspects of the single nucleotide methods currently available for whole genome DNA methylation analyses. Following the success of the standard CpG methylation microarrays for 1,505 CpG sites and 27,000 CpG sites, we have validated in vivo the newly developed 450,000 (450K) cytosine microarray (Illumina). The 450K microarray includes CpG and CNG sites, CpG islands/shores/shelves/open sea, non-coding RNA (microRNAs and long non-coding RNAs) and sites surrounding the transcription start sites (-200 bp to -1,500 bp, 5'-UTRs and exons 1) for coding genes, but also for the corresponding gene bodies and 3'-UTRs, in addition to intergenic regions derived from GWAS studies. Herein, we demonstrate that the 450K DNA methylation array can consistently and significantly detect CpG methylation changes in the HCT-116 colorectal cancer cell line in comparison with normal colon mucosa or HCT-116 cells with defective DNA methyltransferases (DKO). The provided validation highlights the potential use of the 450K DNA methylation microarray as a useful tool for ongoing and newly designed epigenome projects.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draft
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draft
                Role: Formal analysisRole: Writing – original draft
                Role: Resources
                Role: Resources
                Role: Resources
                Role: Resources
                Role: Resources
                Role: Resources
                Role: Resources
                Role: Resources
                Role: Resources
                Role: Funding acquisitionRole: Resources
                Role: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                11 December 2017
                2017
                : 12
                : 12
                : e0189153
                Affiliations
                [1 ] Endocrinology and Nutrition Department, Hospital Universitario Central de Asturias (HUCA), Asturias, Spain
                [2 ] Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, Asturias, Spain
                [3 ] Endocrinology, Nutrition, Diabetes and Obesity Unit, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Asturias, Spain
                [4 ] Surgery Department, Hospital Universitario Central de Asturias, Asturias, Spain
                [5 ] Centro de Investigación en Nanomateriales y Nanotecnología (CINN), El Entrego, Asturias, Spain
                [6 ] Medicine Department, Universidad de Oviedo, Asturias, Spain
                Institut de genomique, FRANCE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                ‡ These authors also contributed equally to this work.

                Author information
                http://orcid.org/0000-0001-6114-9712
                Article
                PONE-D-17-20055
                10.1371/journal.pone.0189153
                5724849
                29228058
                03392d9a-6c9f-4b82-a771-49f118d33584
                © 2017 Rodríguez-Rodero et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 25 May 2017
                : 20 November 2017
                Page count
                Figures: 2, Tables: 3, Pages: 15
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;
                Award ID: PI11/02795
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;
                Award ID: P14/00970
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100008061, Fundación Mutua Madrileña;
                Award Recipient :
                Funded by: Sociedad Española de Diabetes (SED)
                Award Recipient :
                This work was supported by grants from the Fundación Mutua Madrileña (IX Convocatoria de Ayudas para la Investigación Clínica-2012), Instituto de Salud Carlos III (FIS PI11/02795 and FIS P14/00970) and the Sociedad Española de Diabetes (SED) (in 2012).
                Categories
                Research Article
                Biology and life sciences
                Cell biology
                Chromosome biology
                Chromatin
                Chromatin modification
                DNA methylation
                Biology and life sciences
                Genetics
                Epigenetics
                Chromatin
                Chromatin modification
                DNA methylation
                Biology and life sciences
                Genetics
                Gene expression
                Chromatin
                Chromatin modification
                DNA methylation
                Biology and life sciences
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                DNA
                DNA modification
                DNA methylation
                Biology and life sciences
                Biochemistry
                Nucleic acids
                DNA
                DNA modification
                DNA methylation
                Biology and life sciences
                Genetics
                Epigenetics
                DNA modification
                DNA methylation
                Biology and life sciences
                Genetics
                Gene expression
                DNA modification
                DNA methylation
                Medicine and Health Sciences
                Endocrinology
                Endocrine Disorders
                Diabetes Mellitus
                Type 2 Diabetes
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                Diabetes Mellitus
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                Physiology
                Physiological Parameters
                Body Weight
                Obesity
                Medicine and Health Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Obesity
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                Chemical Reactions
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                Anatomy
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                Anatomy
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                Adipose Tissue
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                Biochemistry
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                Endocrinology
                Endocrine Disorders
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