282 Article
Authors
C. Rong1, 2 * , X. Cui2 * , J. Chen2, Y. Qian3, R. Jia3, Y. Hu1
Affiliations
Affiliation addresses are listed at the end of the article
Key words ▶ DNA methylation ● ▶ placenta ● ▶ gestational diabetes mellitus ● ▶ microarray ●
Abstract
received 15.10.2014 first decision 20.01.2015 accepted 20.01.2015 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1398666 Exp Clin Endocrinol Diabetes 2015; 123: 282–288 © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York ISSN 0947-7349 Correspondence Y. Hu Division of Endocrinology Drum Tower Clinical Medical College of Nanjing Medical University Nanjing 210008 China Tel.: + 86/25/6818 2222 61436 Fax: + 86/25/6818 2474 [email protected] R.-Z. Jia Department of Obstetrics Nanjing Medical University Affiliated Nanjing Maternal and Child Health Hospital Nanjing 210004 China Tel.: + 86/25/85891 053 Fax: + 86/25/85891 053 [email protected]
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Emerging evidences indicate that placenta plays a critical role in gestational diabetes mellitus (GDM). DNA methylation could be associated with altered placental development and functions. This study is to uncover the genome-wide DNA methylation patterns in this disorder. DNA methylation was measured at > 385 000 CpG sites using methylated DNA immunoprecipitation (MeDIP) and a huamn CpG island plus promoter microarray. We totally identified 6 641 differentially methylated regions (DMRs) targeting 3 320 genes, of which 2 729 DMRs targeting 1 399 genes, showed significant hypermethylation in GDM relative to the controls, whereas 3 912
Introduction
▼
Gestational diabetes mellitus (GDM) presents during pregnancy in women without pregestational diabetes and typically disappears again after delivery. It affects 3–10 % of all pregnancies in developed countries and is associated with adverse consequences not only during fetal development (i. e., hypoxemia, visceromegaly, hyperbilirubinemia and perinatal mortality) but also later in life, such as obesity, hyperglycaemia, decrease in immune functions as well as cognitive functions [1, 2]. The pathogenesis of GDM have been mainly attributed to insulin resistance and potential islet cell function impairment. It is well known that placenta performs the vital functions of exchange of oxygen, nutrients, antibodies, hormones, and waste products between the mother and fetus. Placental secretion of hormones, such as progesterone, cortisol, placental lactogen, prolactin, and growth hormone, is a major contributor to the insulin-resistant state seen in pregnancy [3]. * These authors contributed equally to this work.
Rong C et al. Placental DNA Methylation in GDM … Exp Clin Endocrinol Diabetes 2015; 123: 282–288
DMRs targeting 1 970 genes showed significant hypomethylation. Functional analysis divided these genes into different functional networks, which mainly involved in the pathways of cell growth and death regulation, immune and inflammatory response and nervous system development. In addition, the methylation profiles and expressions of 4 loci (RBP4, GLUT3, Resistin and PPARα) were validated by BSP for their higher log2 ratio and potential functions with energy metabolism. This study demonstrates aberrant patterns of DNA methylation in GDM which may be involved in the pathophysiology of GDM and reflect the fetal development. Future work will assess the potential prognostic and therapeutic value for these findings in GDM.
Adverse intrauterine environment can alter placetna genes expression and subsequent functions resulting in alterations of infant growth [4]. However, the exact molecular mechanism which causes abnormal expression of the associated genes in placenta is not clear. DNA methylation is a major epigenetic modification that controls gene expression in physiologic and pathologic states [5]. It is involved in the control of genomic imprinting, which is an epigenetic form of gene regulation whereby a gene or genomic domain can be biochemically marked with information about its potential origin [6]. Numerous studies have shown that tissues in the placenta have a high degree of variability in terms of the overall DNA methyalation profile. The promoter methylation of certain genes showed evidences for association with GDM, such as the ADIPOQ, Leptin and Lipoprotein lipase [7–9]. Since these studies lack whole-genome methylation screening, it is necessary to make up a list of human DNA methylation variations in the placenta with GDM. The development of DNA methylation microarray chip provides a powerful method for research in epigenomics.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
DNA Methylation Profiles in Placenta and Its Association with Gestational Diabetes Mellitus
Article 283
Materials and Methods
▼
Subjects
Placental samples were obtained from women who were hospitalized in Nanjing Maternity and Child Health Care Hospital (China) from May 2012 to June 2014. All samples were collected with the approval of the appropriate institutional ethics committee and written consent was given by each pregnant woman. Gestational diabetes was diagnosed based on a 2 h, 75 g oral glucose tolerance test (OGTT) during the second trimester (around 24–28 weeks) [10]. Exclusion criteria for participation include evidences of other pregnancy complications, such as multiple gestation, chronic hypertension, renal or liver disease, serious infections, maternal psychosis, maternal age
Authors
C. Rong1, 2 * , X. Cui2 * , J. Chen2, Y. Qian3, R. Jia3, Y. Hu1
Affiliations
Affiliation addresses are listed at the end of the article
Key words ▶ DNA methylation ● ▶ placenta ● ▶ gestational diabetes mellitus ● ▶ microarray ●
Abstract
received 15.10.2014 first decision 20.01.2015 accepted 20.01.2015 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1398666 Exp Clin Endocrinol Diabetes 2015; 123: 282–288 © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York ISSN 0947-7349 Correspondence Y. Hu Division of Endocrinology Drum Tower Clinical Medical College of Nanjing Medical University Nanjing 210008 China Tel.: + 86/25/6818 2222 61436 Fax: + 86/25/6818 2474 [email protected] R.-Z. Jia Department of Obstetrics Nanjing Medical University Affiliated Nanjing Maternal and Child Health Hospital Nanjing 210004 China Tel.: + 86/25/85891 053 Fax: + 86/25/85891 053 [email protected]
▼
Emerging evidences indicate that placenta plays a critical role in gestational diabetes mellitus (GDM). DNA methylation could be associated with altered placental development and functions. This study is to uncover the genome-wide DNA methylation patterns in this disorder. DNA methylation was measured at > 385 000 CpG sites using methylated DNA immunoprecipitation (MeDIP) and a huamn CpG island plus promoter microarray. We totally identified 6 641 differentially methylated regions (DMRs) targeting 3 320 genes, of which 2 729 DMRs targeting 1 399 genes, showed significant hypermethylation in GDM relative to the controls, whereas 3 912
Introduction
▼
Gestational diabetes mellitus (GDM) presents during pregnancy in women without pregestational diabetes and typically disappears again after delivery. It affects 3–10 % of all pregnancies in developed countries and is associated with adverse consequences not only during fetal development (i. e., hypoxemia, visceromegaly, hyperbilirubinemia and perinatal mortality) but also later in life, such as obesity, hyperglycaemia, decrease in immune functions as well as cognitive functions [1, 2]. The pathogenesis of GDM have been mainly attributed to insulin resistance and potential islet cell function impairment. It is well known that placenta performs the vital functions of exchange of oxygen, nutrients, antibodies, hormones, and waste products between the mother and fetus. Placental secretion of hormones, such as progesterone, cortisol, placental lactogen, prolactin, and growth hormone, is a major contributor to the insulin-resistant state seen in pregnancy [3]. * These authors contributed equally to this work.
Rong C et al. Placental DNA Methylation in GDM … Exp Clin Endocrinol Diabetes 2015; 123: 282–288
DMRs targeting 1 970 genes showed significant hypomethylation. Functional analysis divided these genes into different functional networks, which mainly involved in the pathways of cell growth and death regulation, immune and inflammatory response and nervous system development. In addition, the methylation profiles and expressions of 4 loci (RBP4, GLUT3, Resistin and PPARα) were validated by BSP for their higher log2 ratio and potential functions with energy metabolism. This study demonstrates aberrant patterns of DNA methylation in GDM which may be involved in the pathophysiology of GDM and reflect the fetal development. Future work will assess the potential prognostic and therapeutic value for these findings in GDM.
Adverse intrauterine environment can alter placetna genes expression and subsequent functions resulting in alterations of infant growth [4]. However, the exact molecular mechanism which causes abnormal expression of the associated genes in placenta is not clear. DNA methylation is a major epigenetic modification that controls gene expression in physiologic and pathologic states [5]. It is involved in the control of genomic imprinting, which is an epigenetic form of gene regulation whereby a gene or genomic domain can be biochemically marked with information about its potential origin [6]. Numerous studies have shown that tissues in the placenta have a high degree of variability in terms of the overall DNA methyalation profile. The promoter methylation of certain genes showed evidences for association with GDM, such as the ADIPOQ, Leptin and Lipoprotein lipase [7–9]. Since these studies lack whole-genome methylation screening, it is necessary to make up a list of human DNA methylation variations in the placenta with GDM. The development of DNA methylation microarray chip provides a powerful method for research in epigenomics.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
DNA Methylation Profiles in Placenta and Its Association with Gestational Diabetes Mellitus
Article 283
Materials and Methods
▼
Subjects
Placental samples were obtained from women who were hospitalized in Nanjing Maternity and Child Health Care Hospital (China) from May 2012 to June 2014. All samples were collected with the approval of the appropriate institutional ethics committee and written consent was given by each pregnant woman. Gestational diabetes was diagnosed based on a 2 h, 75 g oral glucose tolerance test (OGTT) during the second trimester (around 24–28 weeks) [10]. Exclusion criteria for participation include evidences of other pregnancy complications, such as multiple gestation, chronic hypertension, renal or liver disease, serious infections, maternal psychosis, maternal age
