Effect of genomic imprinting in placentas on maternal transmission of growth phenotypes to offspring in a multigenerational human cohort study

在多代人类队列研究中，胎盘基因组印记对母亲将生长表型传递给后代的影响

• 批准号: 10366891
• 负责人: Beverly Ilse Strassmann
• 金额: $ 65.79万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366891
• 关键词: 5 year old; Address; Adult; Africa; Age; Alleles; Biological; Birth; Body mass index; Buttocks; Cessation of life; Characteristics; Childhood; Cohort Studies; DNA; DNA Methylation; DNA Sequence; Data; Data Set; Development; Disease; Education; Epigenetic Process; Exons; Fatty acid glycerol esters; Gene Expression; Generations; Genes; Genomic Imprinting; Gestational Age; Growth; Growth and Development function; Head circumference; Health; Height; High-Throughput Nucleotide Sequencing; Human; Individual; Length; Life; Linear Regressions; Locomotion; Mali; Maps; Maternal Age; Measures; Menarche; Methylation; Modeling; Mothers; Nutritional; Oocytes; Parents; Pathway interactions; Phenotype; Placenta; Plant Roots; Play; Population; Positioning Attribute; Puberty; Quality Control; Reporting; Reproducibility; Research; Research Personnel; Resolution; Role; Sampling; Sum; Techniques; Testing; Tissues; Variant; Walking; Weaning; Weight; base; cohort; epigenetic regulation; genome-wide; imprint; improved; innovation; insight; inter-individual variation; interest; life history; low income country; mother nutrition; offspring; parity; phenotypic data; placental malaria; population based; prepregnancy; sex; transcriptome sequencing; transmission process

Strassmann, BI PROJECT SUMMARY Non-communicable diseases (NCDs) are the leading causes of ill health on a global scale and are responsible for seven out of ten deaths. Epigenetic mechanisms play a major role in the developmental origins of NCDs and can transfer information about maternal nutrition to offspring. Genomic imprinting is a mechanism of epigenetic regulation that leads to monoallelic expression of genes based on parent of origin, without regard to DNA sequence. Currently, a major obstacle in the genomic imprinting field is the total lack of longitudinal data on human phenotypes. Such data are needed for understanding why there is so much variability in imprinting between individuals and the functional significance of this variability. This study will test the innovative hypothesis that natural variation in imprinting transmits maternal growth and life history phenotypes to offspring. The researchers collected longitudinal phenotypic data on two generations of mothers and offspring in Mali, West Africa (1998 to 2020). The maternal phenotypes of interest are relevant to NCDs and include body mass index, height, stunting, height-for-age z-score (HAZ) trajectories in childhood, age at puberty and menarche, as well as pre-pregnancy BMI and fat stores (buttocks circumference). The offspring phenotypes include birth parameters, growth trajectories for BMI, height, and HAZ to age 5 years, age at weaning, and age at attainment of developmental milestones for locomotion (sitting without support, standing alone, and walking alone). When the offspring were born, the researchers collected 470 placentas, of which 385 passed quality controls. This study has three specific aims. Aim 1: Test the effects of longitudinally measured maternal nutrition, growth, and life history phenotypes on imprinting in 259 genes in placentas delivered at term. This aim will require the generation of a high-resolution dataset on allele specific expression (ASE) in 385 placentas using a high throughput sequencing technique called “targeted RNAseq.” The targeting region includes the exons of all genes that are known to be imprinted in humans or that are closely associated with differentially methylated regions (DMRs). Aim 2: Test the effects of longitudinally measured maternal nutrition, growth, and life history phenotypes on methylation and hydroxymethylation of both ubiquitous and placenta specific DMRs. Using targeted DNA-methyl sequencing, the researchers will determine the variability in methylation on 1,695 DMRs in 385 placentas. Aim 3: Test the effects of epigenetic read-outs (ASE and DNA methylation) on offspring phenotypes. The results of this study will be significant for understanding why there is so much inter- individual variation in imprinting and DNA methylation. This variability, which presently is of unknown significance, has the potential to be at the crux of diseases that are rooted in deficits and surfeits of maternal nutrition. In sum, this study will provide new insight into the developmental origins of health and disease.

Strassmann，BI 项目摘要 非传染性疾病是全球范围内健康状况不佳的主要原因， 十分之七的死亡都是由它造成的表观遗传机制在非传染性疾病的发育起源中发挥着重要作用 并能将母体营养信息传递给后代。基因组印记是一种 表观遗传调控，导致基因的单等位基因表达的基础上，父母的起源，而不考虑 DNA序列目前，基因组印迹领域的一个主要障碍是完全缺乏纵向数据 人类的表型这些数据是理解为什么有这么多的可变性印记所需要的 以及这种变异性的功能意义。这项研究将测试创新的 印迹的自然变异将母体生长和生活史表型传递给 后代研究人员收集了两代母亲和后代的纵向表型数据 西非马里（1998年至2020年）。感兴趣的母体表型与非传染性疾病相关，包括 体重指数、身高、发育迟缓、儿童期年龄别身高z评分（HAZ）轨迹、青春期年龄和 月经初潮，以及孕前BMI和脂肪储存（臀部周长）。后代表型 包括出生参数、BMI、身高和HAZ至5岁的生长轨迹、断奶年龄和年龄 在达到运动的发育里程碑时（无支撑坐着、独自站立和行走 单独）。当后代出生时，研究人员收集了470个胎盘，其中385个通过质量检测 对照这项研究有三个具体目标。目的1：测试纵向测量的母亲的影响 营养、生长和生活史表型对足月分娩胎盘中259个基因印记的影响。这 一个目标将需要在385个胎盘中产生关于等位基因特异性表达（ASE）的高分辨率数据集 使用一种叫做“靶向RNAseq”的高通量测序技术。靶向区域包括 已知在人类中具有印记的所有基因的外显子，或与差异表达密切相关的所有基因的外显子。 甲基化区域（DMR）。目的2：测试纵向测量的母亲营养、生长和发育的影响。 生活史表型对普遍存在的和胎盘特异性DMR的甲基化和羟甲基化的影响。 使用靶向DNA甲基测序，研究人员将确定1，695个甲基化的变异性。 385个胎盘中的DMR。目的3：测试表观遗传读出（ASE和DNA甲基化）对 后代表型这项研究的结果将是重要的理解为什么有这么多的互- 个体差异和DNA甲基化。这种变异性目前尚不清楚 重要的是，有可能成为根源于产妇营养不足和过量的疾病的关键。 营养总之，这项研究将为健康和疾病的发展起源提供新的见解。