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：
8491926
负责人：
LESLIE MYATT
金额：
$ 22.43万
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 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8491926
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）：诸如母体肥胖之类的环境暴露标记了调节胎盘功能的胎盘表观基因组。肥胖母亲的怀孕通过其炎症环境和代谢危险产生不良的宫内环境，这些危险以性二态性方式以肥胖，糖尿病和成人生活中的代谢疾病为后代进行编程。需要了解宫内环境对胎盘功能的表观遗传调节的作用，以防止代际疾病的传播。表观遗传信息是通过有丝分裂遗传的DNA甲基化和染色质结构的相互作用传达的。使用基因组规模的DNA甲基化阵列，我们发现18个基因具有显着增加的甲基化基因，与正常体重女性相比，该区域的甲基化显着增加，在肥胖症的胎盘中，其转录起始位点的100至 +100bp显着降低。一个具有增加甲基化编码的基因十一易位3（TET3），是酮氯替酸酯和铁依赖性二氧酶的成员超级家族，可将5-甲基8cosin（5MC）转化为5-羟基甲甲基糖苷（5HMC）的基因（5MC）。 5MC和5HMC可以表观遗传控制不同基因集的表达。增加的胎盘TET3启动子甲基化可能会降低TET3表达，降低脱甲基化活性，并与肥胖症启动子甲基化的总体增加有关。我们将检验两个假设：妊娠期间的孕产妇肥胖增加会增加全球DNA甲基化，在某些基因启动子处甲基化与羟甲基的平衡，并改变胎盘和b中的转录特征。 TET3表达可以通过低氧，炎症，氧化还原或代谢应激在胎盘中表观遗传调节。这项高度创新的研究的影响将是对我们对胎盘功能的表观遗传调节的了解的影响，其与肥胖和代谢综合征的发展编程的关系以及所揭示的治疗机会。