Epigenetic alternations of microRNAs and DNA methylation contribute to gestational diabetes mellitus

This study aimed to identify epigenetic alternations of microRNAs and DNA methylation for gestational diabetes mellitus (GDM) diagnosis and treatment using in silico approach. Data of mRNA and miRNA expression microarray (GSE103552 and GSE104297) and DNA methylation data set (GSE106099) were obtained from the GEO database. Differentially expressed genes (DEGs), differentially expressed miRNAs (DEMs) and differentially methylated genes (DMGs) were obtained by limma package. Functional and enrichment analyses were performed with the DAVID database. The protein‐protein interaction (PPI) network was constructed by STRING and visualized in Cytoscape. Simultaneously, a connectivity map (CMap) analysis was performed to screen potential therapeutic agents for GDM. In GDM, 184 low miRNA‐targeting up‐regulated genes and 234 high miRNA‐targeting down‐regulated genes as well as 364 hypomethylation–high‐expressed genes and 541 hypermethylation–low‐expressed genes were obtained. They were mainly enriched in terms of axon guidance, purine metabolism, focal adhesion and proteasome, respectively. In addition, 115 genes (67 up‐regulated and 48 down‐regulated) were regulated by both aberrant alternations of miRNAs and DNA methylation. Ten chemicals were identified as putative therapeutic agents for GDM and four hub genes (IGF1R, ATG7, DICER1 and RANBP2) were found in PPI and may be associated with GDM. Overall, this study identified a series of differentially expressed genes that are associated with epigenetic alternations of miRNA and DNA methylation in GDM. Ten chemicals and four hub genes may be further explored as potential drugs and targets for GDM diagnosis and treatment, respectively.

[1]  A. Pawlik,et al.  The role of genetics and epigenetics in the pathogenesis of gestational diabetes mellitus , 2020, Annals of human genetics.

[2]  Hailan Yang,et al.  Multiple metal concentrations and gestational diabetes mellitus in Taiyuan, China. , 2019, Chemosphere.

[3]  C. Relton,et al.  Epigenetics and gestational diabetes: a review of epigenetic epidemiology studies and their use to explore epigenetic mediation and improve prediction , 2019, Diabetologia.

[4]  Ming-qing Li,et al.  MiR-137 restricts viability and migration of HTR-8/SVneo cells by downregulating FNDC5 in gestational diabetes mellitus. , 2019, Current molecular medicine.

[5]  A. Turgut,et al.  Differential expression of candidate circulating microRNAs in maternal blood leukocytes of the patients with preeclampsia and gestational diabetes mellitus. , 2019, Pregnancy hypertension.

[6]  D. Shechter,et al.  Cellular consequences of arginine methylation , 2019, Cellular and Molecular Life Sciences.

[7]  Jinhua Zhang,et al.  Effect of adoptive transfer of CD4+CD25+Foxp3+ Treg induced by trichostatin A on the prevention of spontaneous abortion. , 2019, Journal of reproductive immunology.

[8]  Xu-Wen Tang,et al.  miR‐335‐5p induces insulin resistance and pancreatic islet β‐cell secretion in gestational diabetes mellitus mice through VASH1‐mediated TGF‐β signaling pathway , 2018, Journal of cellular physiology.

[9]  Yong Zhang,et al.  Integrated Transcriptome Sequencing Analysis Reveals Role of miR-138-5p/ TBL1X in Placenta from Gestational Diabetes Mellitus , 2018, Cellular Physiology and Biochemistry.

[10]  Hongping Lu,et al.  Altered expression of PGC-1α and PDX1 and their methylation status are associated with fetal glucose metabolism in gestational diabetes mellitus. , 2018, Biochemical and biophysical research communications.

[11]  L. Sobrevia,et al.  Foetoplacental epigenetic changes associated with maternal metabolic dysfunction. , 2018, Placenta.

[12]  E. Codner,et al.  Anti-Müllerian hormone in type 2 and gestational diabetes during the second half of pregnancy: relationship with sexual steroid levels and metabolic parameters , 2018, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[13]  S. Salimi,et al.  The association of the placental MTHFR 3′‐UTR polymorphisms, promoter methylation, and MTHFR expression with preeclampsia , 2018, Journal of cellular biochemistry.

[14]  Fabian J Theis,et al.  Maternal whole blood cell miRNA-340 is elevated in gestational diabetes and inversely regulated by glucose and insulin , 2018, Scientific Reports.

[15]  F. Arenas-Huertero,et al.  Central nervous system development-related microRNAs levels increase in the serum of gestational diabetic women during the first trimester of pregnancy , 2017, Neuroscience Research.

[16]  Kai P Law,et al.  Metabolomics in gestational diabetes. , 2017, Clinica chimica acta; international journal of clinical chemistry.

[17]  M. Tadesse,et al.  Circulating early- and mid-pregnancy microRNAs and risk of gestational diabetes. , 2017, Diabetes research and clinical practice.

[18]  S. Kaja,et al.  Regulation of L-type CaV1.3 channel activity and insulin secretion by the cGMP-PKG signaling pathway. , 2017, Cell calcium.

[19]  I. G. Fantus,et al.  The bradykinin-cGMP-PKG pathway augments insulin sensitivity via upregulation of MAPK phosphatase-5 and inhibition of JNK. , 2017, American journal of physiology. Endocrinology and metabolism.

[20]  Zhiguo Chen,et al.  Systematic Characterization of Autophagy in Gestational Diabetes Mellitus , 2017, Endocrinology.

[21]  Muhammad Iqbal,et al.  iACP-GAEnsC: Evolutionary genetic algorithm based ensemble classification of anticancer peptides by utilizing hybrid feature space , 2017, Artif. Intell. Medicine.

[22]  L. Sobrevia,et al.  Insulin/adenosine axis linked signalling. , 2017, Molecular aspects of medicine.

[23]  D. Gaudet,et al.  Placental lipoprotein lipase DNA methylation alterations are associated with gestational diabetes and body composition at 5 years of age , 2017, Epigenetics.

[24]  Ting-Li Han,et al.  Tryptophan and purine metabolites are consistently upregulated in the urinary metabolome of patients diagnosed with gestational diabetes mellitus throughout pregnancy: A longitudinal metabolomics study of Chinese pregnant women part 2. , 2017, Clinica chimica acta; international journal of clinical chemistry.

[25]  F. Slack,et al.  MicroRNA therapeutics: towards a new era for the management of cancer and other diseases , 2017, Nature Reviews Drug Discovery.

[26]  T. Slowinski,et al.  Increased global placental DNA methylation levels are associated with gestational diabetes , 2016, Clinical Epigenetics.

[27]  L. Sobrevia,et al.  Insulin receptor isoforms: an integrated view focused on gestational diabetes mellitus , 2016, Diabetes/metabolism research and reviews.

[28]  L. Myatt,et al.  Sexual dimorphism in activation of placental autophagy in obese women with evidence for fetal programming from a placenta-specific mouse model , 2016, Autophagy.

[29]  Hailing Li,et al.  Profiling maternal plasma microRNA expression in early pregnancy to predict gestational diabetes mellitus , 2015, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[30]  J. Brownell,et al.  Identification of a lung cancer cell line deficient in atg7-dependent autophagy. , 2015, Autophagy.

[31]  R. Jia,et al.  DNA Methylation Profiles in Placenta and Its Association with Gestational Diabetes Mellitus , 2015, Experimental and Clinical Endocrinology & Diabetes (Barth).

[32]  N. Jafari,et al.  Upregulation of microRNA Processing Enzymes Drosha and Dicer in Gestational Diabetes Mellitus , 2015, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[33]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[34]  A. Jawerbaum,et al.  Diabetes-associated changes in the fetal insulin/insulin-like growth factor system are organ specific in rats , 2015, Pediatric Research.

[35]  N. Peachey,et al.  Selective Impairment of a Subset of Ran-GTP-binding Domains of Ran-binding Protein 2 (Ranbp2) Suffices to Recapitulate the Degeneration of the Retinal Pigment Epithelium (RPE) Triggered by Ranbp2 Ablation* , 2014, The Journal of Biological Chemistry.

[36]  W. Foulkes,et al.  DICER1: mutations, microRNAs and mechanisms , 2014, Nature Reviews Cancer.

[37]  O. Larsson,et al.  Nuclear translocation of IGF-1R via p150Glued and an importin-β/RanBP2-dependent pathway in cancer cells , 2014, Oncogene.

[38]  Marie-France Hivert,et al.  Gestational diabetes mellitus epigenetically affects genes predominantly involved in metabolic diseases , 2013, Epigenetics.

[39]  J. Fox,et al.  Connectivity maps for biosimilar drug discovery in venoms: the case of Gila monster venom and the anti-diabetes drug Byetta®. , 2013, Toxicon : official journal of the International Society on Toxinology.

[40]  Marie-France Hivert,et al.  Placental Adiponectin Gene DNA Methylation Levels Are Associated With Mothers’ Blood Glucose Concentration , 2012, Diabetes.

[41]  S. Wiemann,et al.  The Nucleoporin Nup358/RanBP2 Promotes Nuclear Import in a Cargo‐ and Transport Receptor‐Specific Manner , 2012, Traffic.

[42]  I. Haviv,et al.  Epigenetic Regulation of Cell Type–Specific Expression Patterns in the Human Mammary Epithelium , 2011, PLoS genetics.

[43]  I. Lambrinoudaki,et al.  Genetics in gestational diabetes mellitus: association with incidence, severity, pregnancy outcome and response to treatment. , 2010, Current diabetes reviews.

[44]  M. Fraga,et al.  The Possible Role of Epigenetics in Gestational Diabetes: Cause, Consequence, or Both , 2010, Obstetrics and gynecology international.

[45]  Z. Herceg,et al.  Epigenetic interplay between histone modifications and DNA methylation in gene silencing. , 2008, Mutation research.

[46]  Paul A Clemons,et al.  The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease , 2006, Science.

[47]  A. Costantino,et al.  Insulin Receptor Isoform A, a Newly Recognized, High-Affinity Insulin-Like Growth Factor II Receptor in Fetal and Cancer Cells , 1999, Molecular and Cellular Biology.

[48]  T. Haaf,et al.  Identification of a novel Ran binding protein 2 related gene (RANBP2L1) and detection of a gene cluster on human chromosome 2q11-q12. , 1998, Genomics.

[49]  BOULIN,et al.  Classification and Diagnosis of Diabetes. , 2022, Primary care.