Understanding the transgenerational epigenetic effect of maternal psychosocial trauma exposure on infants via lncRNA-sequencing

总结项目 这是麦克莱恩医院、美国哈佛医学院和开普敦之间的合作项目 南非的一所大学建议研究母婴传播的潜在生物学机制 强调婴儿的发展。前瞻性、纵向、母子队列研究发现，儿童 孕期暴露在母体心理压力、抑郁或焦虑中的风险更高。 晚年的行为和情绪问题，包括恐惧、焦虑和抑郁的增加。我们 建议在这项提案中检查RNA介导的表观遗传因素。我们最近发现，患有癌症的成年人 并发PTSD和/或抑郁症(PTSD/MDD)的DICER1基因表达减少，它发挥着一种 通过控制ncRNA的表达，在应激相关途径中发挥中心作用。我们小组的其他新工作 已经显示出一个长的非编码RNA(LncRNA)的差异表达，Gas5直接调节 糖皮质激素受体敏感性，在最近创伤的成年人中作为未来PTSD发展的预测因子。 LncRNAs在体内转录后调节超过一半的蛋白质编码基因的表达。 这项研究将扩展我们成人创伤后应激障碍的发现，DICER1，Gas5和其他lncRNA通路，以阐明 使用综合发展模型的风险跨代传播的潜在机制 德拉肯斯坦的母亲/婴儿队列。在目标1中，我们将重点研究子宫内发育的RNA图谱。我们会 在出生时检查lncRNA和lncRNA介导的表观遗传效应，在宫内暴露于母亲的婴儿中 通过研究患有创伤后应激障碍/MDD的母亲及其婴儿的RNA变化 Drakenstein母婴队列(N=450)。在目标2中，我们将重点关注早期生命发育的RNA图谱。我们 将检验与接触母体有关的lncRNA介导的表观遗传因子的纵向稳定性 出生时、2岁和5岁时的创伤后应激障碍/MDD。我们将确定基于lncRNA的因素是持久的 在出生时暴露于5岁以上的婴儿中的变化，以阐明早期母亲应激的影响 发展，这可能是在以后的生活中表现出负面结果的前奏。在目标3中，我们将重点关注 早期生命核糖核酸图谱和随后的行为发育结果。我们将确定RNA的影响 在出生时、2岁和5岁时对2岁、3.5岁和5岁时的行为和发育测量的概况。在……里面 子宫和环境引起的RNA介导的表观遗传因子表达水平的变化可能 预测行为和情绪问题的发展。通过这些目标中的每一个，该提案将建立 通过培训、实地考察、协作数据分析、出版物和演示文稿增强研究能力。 通过低收入和中等收入国家(LMIC)和中高收入国家之间的合作 国家(UMIC)机构我们将通过基础设施和收集独特的表型和 未来在LMIC中对这一独特的母子队列进行研究的RNA测序数据，推动了我们的 对风险和儿童发展的理解。

SUMMARY PROJECT This collaborative project, between McLean Hospital, Harvard Medical School, USA and Cape Town University, South Africa, proposes to investigate the biological mechanisms underlying effects of maternal stress on infant development. Prospective, longitudinal, mother-child cohort studies have found that children exposed to maternal psychological stress, depression, or anxiety during the prenatal period have higher risk for behavioral and emotional problems later in life, including increased fearfulness, anxiety, and depression. We propose to examine RNA-mediated epigenetic factors in this proposal. We recently found that adults with comorbid PTSD and/or Depression (PTSD/MDD) have reduced expression of the DICER1 gene, which plays a central role in stress-related pathways by controlling ncRNA expression. Additional new work from our group has shown differential expression of a long non-coding RNA (lncRNA), GAS5, which directly regulates glucocorticoid receptor sensitivity, in recently traumatized adults as a predictor of later PTSD development. lncRNAs regulate expression of more than half of all protein-coding genes post-transcriptionally in the body. This study will extend our adult PTSD findings of DICER1, GAS5 and other lncRNA pathways, to elucidate mechanisms underlying transmission of risk across generations using an integrative developmental model in the Drakenstein mother/infant cohort. In aim 1, we will focus on in utero developmental RNA profiles. We will examine lncRNA and lncRNA-mediated epigenetic effects at birth, in infants exposed in utero to maternal PTSD/MDD by investigating RNAs that are altered in both mothers with PTSD/MDD and their infants in the Drakenstein mother/infant cohort (N=450). In aim 2, we will focus on early life developmental RNA profiles. We will examine longitudinal stability of lncRNA-mediated epigenetic factors associated with exposure to maternal PTSD/MDD at birth and at age 2 and 5 years. We will identify lncRNA-based factors that are persistently altered in exposed infants at birth across age 5 to elucidate the effects of maternal stress during early life development, which may prelude to manifestation of negative outcomes later in life. In aim 3, we will focus on early life RNA profiles and subsequent behavioral-developmental outcomes. We will identify the effects of RNA profiles at birth, age 2 and 5 years on behavioral and developmental measures at ages 2, 3.5 and 5 years. In utero and environmentally induced changes in expression levels of RNA-mediated epigenetic factors may predict development of behavioral and emotional problems. Through each of these aims, the proposal will build research capacity through training, site visits, collaborative data analyses, publications, and presentations. Through collaboration between the low- and middle-income country (LMIC) and upper- and middle-income country (UMIC) institutions we will lay foundation via infrastructure and collection of unique phenotypes and RNA-sequencing data for future studies of this unique mother-child cohort in the LMIC, advancing our understanding of risk and child development.