A longitudinal study of loss of imprinting in the placenta

胎盘印记丢失的纵向研究

• 批准号: 8191917
• 负责人: Men-Jean Lee
• 金额: $ 29.09万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-25 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191917
• 关键词: Alleles; Biological Assay; Biological Markers; Birth; Cardiovascular Diseases; Case-Control Studies; Child; Chorionic Villi Sampling; Chorionic villi; Cohort Studies; DNA Methylation; Data; Development; Diet and Nutrition; Disease; Embryo; Embryonic Development; Enrollment; Environment; Epigenetic Process; Fertilization; Fetal Growth Retardation; First Pregnancy Trimester; Functional disorder; Gene Dosage; Genes; Genome; Genomic Imprinting; Human; Human Genome; Knowledge; Lead; Longevity; Longitudinal Studies; Measures; Methodology; Methylation; Monitor; Mono-S; Morbidity - disease rate; Mothers; National Institute of Child Health and Human Development; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organism; Outcome; Outcome Study; Pattern; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnant Women; Premature Labor; Prenatal Diagnosis; Prevention strategy; Public Health; Recruitment Activity; Research Design; Reverse Transcriptase Polymerase Chain Reaction; Sampling; Specimen; Structure of primordial sex cell; Term Birth; Time; Villus; Woman; base; cohort; dosage; environmental change; fetal medicine; histone modification; human disease; imprint; improved; innovation; mortality; novel; postnatal; preterm premature rupture of membranes; programs; prospective; theories; trophoblast

DESCRIPTION (provided by applicant): For most human genes, maternal and paternal alleles are bi-allelically expressed. However, a specific subset of genes are imprinted and mono-allelically expressed. The current dogma is that this embryonic imprint is stable across the lifespan of the organism. Loss of imprinting (LOI) leads to bi-allelic expression of the imprinted gene, potentially causing a doubling of gene dosage or gene dysregulation, resulting in disease. Because the methylation marks of imprinted genes are considered permanent after fertilization, any acquired changes in the intrauterine environment may lead to stable transgenerational effects. The regulatory complexity of these imprinted gene domains may render them particularly sensitive to environmental changes such as diet and nutrition. Emerging evidence implicates aberrant imprinting in the pathophysiology of many common human diseases, including complications of pregnancy such as intrauterine growth restriction (IUGR) and preeclampsia (PE); and even postnatal disorders such as obesity, cardiovascular disease, and type 2 diabetes. We have developed a highly sensitive and quantitative allele-specific PCR analysis to measure LOI in a panel of imprinted genes in the human genome. Using this methodology, we have already determined that pregnancies complicated by PE and IUGR are associated with dysregulation of a set of imprinted genes in the placenta. Both of these obstetrical disorders have their origins in an early intrauterine environment associated with aberrant placentation and trophoblast invasion. We also have novel evidence to suggest that genomic imprinting patterns are not permanently fixed in placental development. Contrary to the prevailing theory, we hypothesize that patterns of LOI are not static in the human placenta and are subject to developmental and environmental influences over the course of pregnancy that predispose to adverse pregnancy outcome. We now propose a longitudinal trial as a secondary study to the NuMOM2B Trial to monitor LOI in placenta samples from first trimester CVS to birth and determine which LOI patterns in the first trimester lead to normal pregnancy outcomes and which patterns are predictive of pregnancy complications. PUBLIC HEALTH RELEVANCE: We have novel preliminary data to suggest that genomic imprinting in the human placenta takes place across gestation and is not permanently fixed in early pregnancy. We seek to confirm this finding in a longitudinal study of loss of imprinting by monitoring placenta samples from chorionic villus sampling in the first trimester and the same respective placentas at birth. We will also explore how differences in loss of imprinting patterns in first trimester placenta samples may be predictive of pregnancy complications which can ultimately be developed into a bioassay for adverse pregnancy outcomes.

描述（由申请人提供）：对于大多数人类基因，母本和父本等位基因是双等位基因表达的。然而，特定的基因子集被印记并单等位基因表达。目前的教条是，这种胚胎印记在生物体的整个生命周期中都是稳定的。印记丢失 (LOI) 会导致印记基因的双等位基因表达，可能导致基因剂量加倍或基因失调，从而导致疾病。由于印记基因的甲基化标记在受精后被认为是永久性的，因此宫内环境的任何后天变化都可能导致稳定的跨代效应。这些印记基因域的调控复杂性可能使它们对饮食和营养等环境变化特别敏感。新出现的证据表明，许多常见人类疾病的病理生理学中存在异常印记，包括妊娠并发症，如宫内生长受限（IUGR）和先兆子痫（PE）；甚至肥胖、心血管疾病和 2 型糖尿病等产后疾病。我们开发了一种高度灵敏、定量的等位基因特异性 PCR 分析方法，用于测量人类基因组中一组印记基因的 LOI。使用这种方法，我们已经确定，PE 和 IUGR 并发的妊娠与胎盘中一组印记基因的失调有关。这两种产科疾病都起源于与异常胎盘和滋养层侵袭相关的早期宫内环境。我们还有新的证据表明基因组印记模式在胎盘发育中并不是永久固定的。与流行的理论相反，我们假设人类胎盘中的 LOI 模式不是静态的，并且在怀孕过程中会受到发育和环境的影响，从而容易导致不良妊娠结局。我们现在提出一项纵向试验，作为 NuMOM2B 试验的二次研究，监测从妊娠早期 CVS 到出生的胎盘样本中的 LOI，并确定妊娠早期的哪些 LOI 模式会导致正常妊娠结果，哪些模式可以预测妊娠并发症。 公共健康相关性：我们有新的初步数据表明，人类胎盘中的基因组印记发生在整个妊娠期，并且在妊娠早期并未永久固定。我们试图通过监测妊娠早期绒毛膜绒毛取样的胎盘样本和出生时的相同胎盘样本，在印记丢失的纵向研究中证实这一发现。我们还将探讨妊娠早期胎盘样本中印迹模式丢失的差异如何预测妊娠并发症，最终可开发为不良妊娠结局的生物测定。