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

• 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
• 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

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(申请人提供)：环境暴露，如母亲肥胖，标志着调节胎盘功能的胎盘表观基因组。肥胖母亲的怀孕产生了不利的宫内环境，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规划肥胖、糖尿病和代谢性疾病。了解宫内环境对胎盘功能的表观遗传调节的作用对于预防疾病的代际传播是必要的。表观遗传信息通过DNA甲基化的有丝分裂遗传模式和染色质结构的相互作用来传递。利用基因组规模的DNA甲基化阵列，我们发现与正常体重的女性相比，肥胖胎盘中有18个基因的甲基化显著增加，3个基因的甲基化显著降低，位于其转录起始点的-100至+100bp区域。一个甲基化增加的基因编码10-11易位3(TET3)，它是酮戊二酸和铁依赖的双加氧酶超家族的成员，将5-甲基胞嘧啶(5mC)转化为5-羟甲基胞嘧啶(5hmC)，并受代谢环境的调节。5mC和5hmC可能在表观遗传上控制不同基因的表达。胎盘TET3启动子甲基化增加可能会降低TET3的表达，降低去甲基化活性，并与肥胖患者启动子甲基化的总体增加有关。 我们将检验两个假说：a.妊娠期间增加的母亲肥胖增加了全局DNA甲基化，某些基因启动子上的甲基化和羟甲基化的平衡，并改变了胎盘的转录谱；b.胎盘中TET3的表达可以通过缺氧、炎症、氧化还原或代谢应激进行表观遗传调节。这项极具创新性的研究的影响将是我们对母体肥胖对胎盘功能的表观遗传调节、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的认识的增加对总体人群健康的影响。