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.

Strassmann，Bi 项目摘要 非通信疾病（NCD）是全球范围内健康状况不佳的主要原因，负责 十分之七的死亡。表观遗传机制在NCD的发育起源中起主要作用 并可以将有关孕产妇营养的信息转移到后代。基因组印记是 表观遗传调节，导致基因基于原始父的单相表达，而无需考虑 DNA序列。目前，基因组烙印领域的主要障碍是完全缺乏纵向数据 关于人类表型。需要这样的数据来理解为什么烙印如此之多 个人与这种变异性的功能意义。这项研究将测试创新性 假设自然变化在烙印传输材料生长和生活史表型中 后代。研究人员收集了两代母亲和后代的纵向表型数据 在西非马里（1998年至2020年）。感兴趣的母亲表型与NCD有关，包括 体重指数，身高，发育迟缓，童年时代的Z分数（HAZ）轨迹，青春期的年龄和 初潮以及怀孕前的BMI和脂肪储存（臀部循环）。后代表型 包括出生参数，BMI的生长轨迹，高度和5岁的HAZ，断奶时的年龄和年龄 达到运动的发展里程碑（无支撑坐着，独自站立和行走） 独自的）。后代诞生时，研究人员收集了470个plecetas，其中385张通过了质量 控件。这项研究具有三个具体目标。目标1：测试纵向测量的母体的影响 术语传递的259个基因印迹的营养，生长和生活史表型。这 AIM将需要在385个位置上生成等位基因表达式（ASE）上的高分辨率数据集 使用称为“靶向RNASEQ”的高吞吐量测序技术。目标区域包括 所有已知在人类中具有印记或与差异相关的基因的外显子 甲基化区域（DMR）。目标2：测试纵向测量的母体营养，生长和 生命史表型对普遍存在和胎盘特异性DMR的甲基化和羟甲基化的表型。 使用靶向的DNA-甲基测序，研究人员将确定1,695的甲基化变化 DMR在385个plecetas中。目标3：测试表观遗传学读出（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这么多的间 烙印和DNA甲基化的个体变异。这种可变性是未知的 意义，有可能处于植根于孕产妇的疾病和疾病的关键 营养。总而言之，这项研究将为健康和疾病的发展起源提供新的见解。