Effects of a Maternal Obesogenic Environment on DNA Methylation in the Placenta

母体肥胖环境对胎盘 DNA 甲基化的影响

基本信息

批准号：
8707875
负责人：
LESLIE MYATT
金额：
$ 13.76万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2015-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8707875
关键词：
Adult Body Weight Cell Culture Techniques Chromatin Chromatin Structure DNA DNA Methylation Development Diabetes Mellitus Dioxygenases Disease Environment Environmental Exposure Enzymes Epidemic Epigenetic Process Equilibrium Exploratory/Developmental Grant Fetal Development Fetal Growth Fetal Growth Retardation Fetus Gene Expression Genes Genetic Transcription Genome Genomics Gestational Age Health Hypermethylation Hypoxia Immunoprecipitation Individual Inflammation Inflammatory Iron Knowledge Life Link Mammals Measurement Mediating Metabolic Metabolic Diseases Metabolic stress Metabolic syndrome Methods Methylation Modification Mothers Nutritional status Obesity Oxidation-Reduction Oxygen measurement, partial pressure, arterial Pattern Physiological Placenta Pre-Eclampsia Pregnancy Pregnancy Outcome Process Promoter Regions Proteins Regulation Reverse Transcriptase Polymerase Chain Reaction Role Testing Therapeutic Third Pregnancy Trimester Tissues Transcription Initiation Site Variant Western Blotting Woman base demethylation disease transmission epigenome fetal gene function gene repression high risk in utero innovation intergenerational mRNA Expression member novel offspring population health prevent programs promoter protein expression public health relevance pyrosequencing sexual dimorphism trophoblast

项目摘要

DESCRIPTION (provided by applicant): Environmental exposures such as maternal adiposity mark the placental epigenome which modulates placental function. Pregnancies in obese mothers generate an adverse intrauterine environment, via their inflammatory milieu and metabolic derangements that programs the offspring in a sexually dimorphic manner for obesity, diabetes and metabolic disease in adult life. Understanding the role of the intrauterine environment on epigenetic regulation of placental function is needed to prevent the intergenerational transmission of disease. Epigenetic information is conveyed via the interaction of mitotically heritable patterns of DNA methylation and chromatin structure. Using a genome-scale DNA methylation array we find 18 genes with significantly increased methylation, and 3 genes with significantly decreased methylation, in the region from - 100 to +100bp of their transcription start sites in placentas of obese compared to normal body weight women. One gene with increased methylation encodes for ten eleven translocation 3 (TET3), a member of a ketoglutarate and iron-dependent dioxygenase enzyme superfamily, that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and can be regulated by the metabolic environment. 5mC and 5hmC may epigenetically control expression of distinct sets of genes. Increased placental TET3 promoter methylation may decrease TET3 expression, reduce demethylation activity and be linked to the overall increase in promoter methylation with obesity. We will test two hypotheses: a. increasing maternal adiposity during pregnancy increases global DNA methylation, the balance of methylation to hydroxymethylation at certain gene promoters and alters the transcriptional profile in placenta and b. TET3 expression can be epigenetically regulated in the placenta by hypoxic, inflammatory, redox or metabolic stress. The impact of this highly innovative study will be the effect on overall population health of our increased knowledge of the epigenetic regulation of placental function by maternal adiposity, its relationship to the developmental programming of obesity and metabolic syndrome and the therapeutic opportunities revealed.

描述（由申请人提供）：母亲肥胖等环境暴露标志着调节胎盘功能的胎盘表观基因组。肥胖母亲怀孕时会产生不利的宫内环境，通过炎症环境和代谢紊乱，使后代在成年后以性别二态的方式患上肥胖、糖尿病和代谢疾病。为了预防疾病的代际传播，需要了解宫内环境对胎盘功能表观遗传调节的作用。表观遗传信息是通过 DNA 甲基化和染色质结构的有丝分裂遗传模式的相互作用来传递的。使用基因组规模的 DNA 甲基化阵列，我们发现与正常体重女性相比，肥胖女性胎盘转录起始位点的 - 100 至 +100bp 区域有 18 个甲基化显着增加的基因和 3 个甲基化显着减少的基因。甲基化增加的一个基因编码 10-11 易位 3 (TET3)，TET3 是酮戊二酸和铁依赖性双加氧酶超家族的成员，可将 5-甲基胞嘧啶 (5mC) 转化为 5-羟甲基胞嘧啶 (5hmC)，并且可以通过代谢环境。 5mC 和 5hmC 可能在表观遗传上控制不同基因组的表达。胎盘 TET3 启动子甲基化增加可能会降低 TET3 表达，降低去甲基化活性，并与肥胖引起的启动子甲基化总体增加有关。我们将检验两个假设：怀孕期间母亲肥胖的增加会增加整体 DNA 甲基化、某些基因启动子处甲基化与羟甲基化的平衡，并改变胎盘中的转录谱。 TET3 的表达可以在胎盘中通过缺氧、炎症、氧化还原或代谢应激进行表观遗传调节。这项高度创新的研究的影响将是我们对孕产妇肥胖对胎盘功能的表观遗传调控的认识的增加，对总体人口健康的影响，其与肥胖和代谢综合征的发育规划的关系以及所揭示的治疗机会。