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

总结项目 美国哈佛医学院姆克林医院和开普敦的合作项目 南非大学的研究人员提出，要研究产妇分娩后， 强调婴儿发展。前瞻性、纵向、母婴队列研究发现， 在产前期间暴露于母亲心理压力、抑郁或焦虑的孕妇， 行为和情绪问题，包括增加恐惧，焦虑和抑郁。我们 在这个提议中，我建议检查RNA介导的表观遗传因素。我们最近发现， 共病PTSD和/或抑郁症（PTSD/MDD）的DICER 1基因表达减少，DICER 1基因在PTSD和/或抑郁症中起作用。 通过控制ncRNA表达在应激相关途径中发挥重要作用。我们小组的其他新工作 已经显示出一种长的非编码RNA（lncRNA）GAS 5的差异表达，GAS 5直接调节 糖皮质激素受体敏感性，在最近创伤的成年人作为预测后期PTSD的发展。 lncRNA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对DICER 1，GAS 5和其他lncRNA通路的成人PTSD研究结果，以阐明 使用综合发展模型探讨风险代际传递的潜在机制， 德拉肯斯坦母婴群体在目标1中，我们将专注于子宫内发育RNA谱。我们将 检查lncRNA和lncRNA介导的表观遗传效应在出生时，婴儿在子宫内暴露于母亲 研究PTSD/MDD母亲及其新生儿中改变的RNA， Drakenstein母亲/婴儿队列（N=450）。在目标2中，我们将专注于早期生命发育RNA谱。我们 将研究与暴露于母体相关的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PTSD/MDD。我们将识别出持续存在的基于lncRNA的因子， 在出生时暴露于5岁以下的婴儿中发生改变，以阐明母亲压力在生命早期的影响 发展，这可能预示着在以后的生活中出现负面结果。在目标3中，我们将重点关注 早期生命RNA谱和随后的行为发育结果。我们将确定RNA的作用 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 子宫和环境诱导的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。通过每一个目标，该提案将建立 通过培训、实地考察、协作数据分析、出版物和演示提高研究能力。 通过中低收入国家与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奠定基础， RNA测序数据用于LMIC中这一独特母子队列的未来研究， 了解风险和儿童发展。

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.