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: 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
• 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

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（由申请方提供）：环境暴露（如母体肥胖）标志着调节胎盘功能的胎盘表观基因组。肥胖母亲的妊娠通过其炎症环境和代谢紊乱产生不利的宫内环境，其以性二态的方式编程后代在成年后患肥胖症、糖尿病和代谢疾病。需要了解宫内环境对胎盘功能表观遗传调节的作用，以防止疾病的代际传播。 表观遗传信息通过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。使用基因组规模的DNA甲基化阵列，我们发现18个基因的甲基化显着增加，和3个基因的甲基化显着降低，在其转录起始位点的区域从-100到+100 bp的肥胖妇女相比，正常体重的妇女胎盘。一个甲基化增加的基因编码10 - 11易位3（TET 3），TET 3是酮戊二酸和铁依赖性双加氧酶超家族的成员，其将5-甲基胞嘧啶（5 mC）转化为5-羟甲基胞嘧啶（5 hmC），并且可以由代谢环境调节。5 mC和5 hmC可以表观遗传地控制不同基因组的表达。胎盘TET 3启动子甲基化的增加可能会降低TET 3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。 我们将测试两个假设：A。怀孕期间母体肥胖的增加增加了整体DNA甲基化，某些基因启动子处甲基化与羟甲基化的平衡，并改变了胎盘和B中的转录谱。TET 3的表达可以通过缺氧、炎症、氧化还原或代谢应激在胎盘中进行表观遗传调节。 这项高度创新的研究的影响将是我们对母体肥胖对胎盘功能的表观遗传调节的认识增加对整体人群健康的影响，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。