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

斯特拉斯曼，BI 项目总结 非传染性疾病(NCDs)是全球范围内健康状况不佳的主要原因，是 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起主要作用 并且可以将有关母亲营养的信息传递给后代。基因组印记是一种 表观遗传调控，导致基于起源亲本的基因单等位基因表达，而不考虑 DNA序列。目前，基因组印迹领域的一个主要障碍是完全缺乏纵向数据 关于人类的表型。需要这样的数据才能理解印记为什么会有如此大的变异性 个体与个体之间这种变异性的功能意义。这项研究将测试创新的 假设印记中的自然变异将母亲的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 在西非马里(1998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、儿童时期身高Z分数(HAZ)轨迹、青春期年龄和 月经初潮，以及孕前体重指数和脂肪储存(臀围)。后代的表型 包括出生参数、BMI、身高和HAZ到5岁、断奶年龄和年龄的生长轨迹 达到运动发育的里程碑(无支撑坐着、独自站立和走路 单独)。当后代出生时，研究人员收集了470个胎盘，其中385个合格 控制。这项研究有三个具体目标。目的1：测试纵向测量的母体的影响 足月分娩胎盘中259个基因的营养、生长和生活史表型。这 AIM将要求生成关于385个胎盘的等位基因特异性表达(ASE)的高分辨率数据集 使用一种称为“靶向RNAseq”的高通量测序技术。目标区域包括 所有已知在人类身上有印记或与差异密切相关的基因的外显子 甲基化区域(DMRS)。目的2：测试纵向测量的母体营养、生长和 无处不在的和胎盘特异的DMR的甲基化和羟甲基化的生活史表型。 使用定向DNA-甲基测序，研究人员将确定1,695位甲基化的变异性 385例胎盘中有DMRS。目的3：测试表观遗传读出(ASE和DNA甲基化)对 后代的表型。这项研究的结果将对理解为什么有如此多的 印记和DNA甲基化的个体差异。这种变化性，目前是未知的 有可能成为根植于母体营养不足和过量的疾病的症结所在。 营养。总而言之，这项研究将为健康和疾病的发育起源提供新的见解。

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.