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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：
9276325
负责人：
LESLIE MYATT
金额：
$ 4.4万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
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 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9276325
关键词：
Effects Maternal Obesogenic Environment DNA

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）：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。肥胖母亲的怀孕通过炎症环境和代谢紊乱产生不利的宫内环境，使后代在成年后以两性二态的方式患上肥胖症、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控的作用是预防疾病代际传播的必要条件。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。利用基因组尺度的DNA甲基化阵列，我们发现与正常体重妇女相比，肥胖妇女胎盘中有18个基因甲基化显著增加，3个基因甲基化显著降低，其转录起始位点在- 100到+100bp之间。一个甲基化增加的基因编码10 - 11易位3 (TET3)，这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），并可受代谢环境调节。5mC和5hmC可能在表观遗传学上控制不同基因的表达。胎盘TET3启动子甲基化的增加可能会降低TET3表达，降低去甲基化活性，并与肥胖启动子甲基化的总体增加有关。