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: 10544147
• 负责人: Beverly Ilse Strassmann
• 金额: $ 65.8万
• 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/10544147
• 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; Fertilization; 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; Play; Population; Positioning Attribute; Puberty; Quality Control; Reporting; Repression; Reproducibility; Research; Research Personnel; Resolution; Role; Sampling; Techniques; Testing; Tissues; Variant; Walking; Weaning; Weight; 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.

斯特拉斯曼，BI 项目概要 非传染性疾病 (NCD) 是全球范围内健康不良的主要原因， 十分之七的死亡。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 并可以将母体营养信息传递给后代。基因组印记是一种机制 表观遗传调控导致基于亲本的基因单等位基因表达，而不考虑 DNA 序列。目前，基因组印记领域的一个主要障碍是完全缺乏纵向数据 关于人类表型。需要这些数据来理解为什么印记存在如此大的变异性 个体之间以及这种差异的功能意义。这项研究将测试创新 假设印记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、儿童时期的年龄别身高 Z 值 (HAZ) 轨迹、青春期年龄和 初潮，以及怀孕前的体重指数和脂肪储存（臀部周长）。后代表型 包括出生参数、BMI、身高和 5 岁时 HAZ 的生长轨迹、断奶年龄和年龄 达到运动发育里程碑（无需支撑坐、独自站立和行走） 独自的）。当后代出生时，研究人员收集了470个胎盘，其中385个通过了质量检查 控制。这项研究有三个具体目标。目标 1：测试纵向测量孕产妇的影响 足月胎盘中 259 个基因印记的营养、生长和生活史表型。这 目标将需要生成 385 个胎盘等位基因特异性表达 (ASE) 的高分辨率数据集 使用称为“靶向RNAseq”的高通量测序技术。目标区域包括 已知在人类中印记或与差异密切相关的所有基因的外显子 甲基化区域（DMR）。目标 2：测试纵向测量的孕产妇营养、生长和发育的影响 普遍存在的和胎盘特异性 DMR 的甲基化和羟甲基化的生活史表型。 使用靶向 DNA 甲基测序，研究人员将确定 1,695 上甲基化的变异性 385 个胎盘中的 DMR。目标 3：测试表观遗传读数（ASE 和 DNA 甲基化）对 后代表型。这项研究的结果对于理解为什么存在如此多的相互影响具有重要意义。 印记和 DNA 甲基化的个体差异。这种变化目前尚不清楚 重要性，有可能成为根源于孕产妇营养不足和过多的疾病的症结所在 营养。总之，这项研究将为健康和疾病的发育起源提供新的见解。