Characterizing the functional genomic atlas of human placenta and unveiling the prenatal programming of early-life development

摘要/摘要 相当大比例的出生后健康，包括儿童肥胖和代谢性疾病，都是程序化的 在胎儿发育过程中的子宫内。虽然出生体重与这些结果有关，但它可能只是一个指标 反映了基因和环境的复杂相互作用，定义了出生体重之间的共同病因 和晚年的生活健康，这定义了健康和疾病的发育起源(DOHAD)假说。 支持这一假设的是一些大型的全基因组关联研究(GWAS)，这些研究已经 确定了与早期生活结果相关的基因变异，如出生体重和儿童肥胖、身体 体重指数和肥胖症，并已证明这些相同的变异也可以影响成年人 心血管特征和疾病。因此，早期干预，通过识别高危人群和/或 针对由遗传和环境因素引起的功能变异，可能在 减轻总体疾病负担。我们的团队带头进行了胎盘研究，表明胎盘 可能是许多儿童健康规划的关键器官。这项提案的框架是 认为胎盘的功能基因组是子宫内发育的关键和唯一媒介的假说 环境(遗传和非遗传)影响出生体重和计划出生后生长和 这种影响可能发生在胎盘的特定细胞成分上。利用 美国三个特征良好和多样化的出生队列的资源，我们提出了一个严格的综合 基因组学和系统生物学研究，以证明胎盘在疾病中的因果机制作用 使用最先进的出生后健康规划、出生后、功能基因组研究，包括 单核RNA测序技术和分子数量性状基因座分析的创新应用 (MolQTL)。我们将建立一个全面的人类足月胎盘分子图谱，以确定功能 调节出生体重的分子特征以及那些独立于遗传学的GWA值，我们将 建立细胞分辨率的胎盘转录图谱，以提高对胎盘转录的作用机制的理解。 单细胞水平的胎盘。此外，我们将研究出生体重与未来的关联- 5岁时胎盘生长轨迹、儿童肥胖、体重指数和肥胖症的相关分子特征 胎盘在长期健康规划中的作用的典范。这个项目与研究的优先顺序一致。 NICHD的妊娠和围产期分会，在定义 “正常和异常胎盘”以及对妊娠产生不利影响的遗传和表观遗传因素 结果“。我们的研究结果将为基于胎盘的生物标记物的开发铺平道路 在出生时对儿童进行前瞻性风险分层评估，以便可以实施早期干预； 它们还将帮助确定有助于确定预防或干预战略的机械途径 减轻长期疾病负担。

SUMMARY/ABSTRACT A substantial proportion of postnatal health, including childhood obesity and metabolic disease, is programmed in utero during fetal development. While birthweight has been linked to these outcomes, it may be only a proxy reflecting a complex interplay of genetics and environment that defines a common etiology between birthweight and later life health, and which defines the Developmental Origins of Heath and Disease (DOHaD) hypothesis. Supporting this hypothesis are a number of large, genome-wide association studies (GWAS) that have identified genetic variants associated with early life outcomes, such as birthweight and childhood obesity, body mass index and adiposity, and have demonstrated that these same variants can also impact adult cardiovascular traits and disease. Thus, early intervention, either through identifying at-risk population and/or targeting functional variations induced by genetic and environmental factors, could be highly effective in reducing overall disease burden. Our team spearheaded the placental research suggesting that the placenta may be the critical organ for much of childhood health programming. This proposal is framed on the hypothesis that the functional genome of a placenta acts as a critical and unique mediator of the in utero environment (both genetic and non-genetic) to influence birthweight and program postnatal growth and development, and such effects may occur in particular cellular components of the placenta. Leveraging the resources of three well-characterized and diverse birth cohorts in the US, we propose a rigorous integrative genomics and systems biology investigation to demonstrate the causal, mechanistic role of the placenta in postnatal health programming using state-of-the-art, post-GWAS, functional genomic investigations, including innovative use of single-nucleus RNA sequencing technology and molecular quantitative trait loci analyses (molQTL). We will build a comprehensive molecular atlas of human term placenta to identify functional molecular features that mediate birthweight GWAS hits as well as those independent of genetics, and we will build a placental transcriptomic atlas at cellular resolution to improve mechanistic understanding of the role of the placenta at the single cell level. Furthermore, we will examine prospective associations of the birthweight- related molecular features in placenta with growth trajectory, childhood obesity, BMI, and adiposity at age 5 as a model of the placenta’s role in long-term health programming. This project aligns with the research priorities of Pregnancy and Perinatology Branch of the NICHD, in defining “molecular biology processes involved in normal and abnormal placentation” as well as “genetic and epigenetic factors that adversely affect pregnancy outcomes”. Results from our study will pave the way for the development of placenta-based biomarkers to be assessed at birth for prospective risk stratification into childhood so early intervention may be implemented; they will also help identify mechanistic pathways useful in defining prevention or intervention strategies to alleviate long-term disease burden.