Placental epigenetic mechanisms contributing to sex-specific impacts of maternal stress on fetal development

胎盘表观遗传机制导致母体压力对胎儿发育的性别特异性影响

• 批准号: 10563162
• 负责人: Tracy L Bale
• 金额: $ 52.36万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-11 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563162
• 关键词: Affect; Attention deficit hyperactivity disorder; Biochemical; Birth; Brain; Cells; Development; EZH2 gene; Environment; Epigenetic Process; Female; Fetal Development; Fetus; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Glucocorticoids; Growth; Histones; Human; Hypothalamic structure; Link; Metabolic; Metabolic dysfunction; Methods; Methylation; Methyltransferase; MicroRNAs; Mitochondria; Modeling; Molecular; Molecular Target; Mus; Neurodevelopmental Disorder; Neurons; Nuclear; O-GlcNAc transferase; Outcome; Perfusion; Phenotype; Placenta; Predictive Factor; Pregnancy; Proteomics; Puberty; Regulation; RiboTag; Risk; Sex Bias; Sex Chromosomes; Sex Differences; Sex Ratio; Signal Transduction; Stress; Testing; Time; Tissues; Transcriptional Regulation; Transferase; Transgenic Mice; Transgenic Organisms; Weaning; Weight; autism spectrum disorder; boys; disorder risk; ex vivo perfusion; fetal; gene repression; genome wide screen; genome-wide; girls; in utero; innovation; male; maternal stress; metabolomics; mitochondrial dysfunction; mitochondrial messenger RNA; mouse model; offspring; outcome prediction; prenatal; prenatal stress; programs; resilience; response; sex; steroid hormone; transcriptome; trophoblast

Defining the mechanisms by which stress in the environment during pregnancy promotes changes in development is critical in identifying factors predictive of disease risk or resilience. One major consistency across prenatal insults is the increased vulnerability of males. In this proposal, we utilize our mouse model of early prenatal stress (EPS) to examine sex-specific placental transcriptional regulation. In our EPS model, male, but not female, offspring present with increased stress sensitivity, including increased HPA stress axis activity, reduced post-weaning growth, and hypothalamic mitochondrial dysfunction. Sex differences in the placental function are likely to produce sex-specific transplacental signals to the developing fetal brain. Sex differences in the placenta begin with sex chromosomes. Through a genome-wide screen following maternal stress, we identified the X-linked gene, OGT, as causal in programming the male-specific stress phenotype via its regulation of the histone transcriptional repressive mark, H3K27me3. This proposal uses innovative approaches to determine the mechanisms by which the female placenta is able to restrict transcriptional responses to stress in the environment, where males are not, thus placing the male developing brain at greater risk prenatally. The transplacental signals received by the developing brain appear to be related to energy availability and impact metabolic and mitochondrial programming. Of key translational importance, we have also found the same biochemical and molecular outcomes are predicted by fetal sex in human placental tissue. Therefore, our proposal will focus on defining the causal importance of H3K27me3 in risk for developmental changes in response to stress, identify the sex-specific transplacental signals resulting from these changes in placental function using ex vivo perfusion, and determine the cellular compartment and mechanism by which these changes promote hypothalamic mitochondrial reprogramming and the EPS phenotype.

定义怀孕期间环境压力促进变化的机制 发展对于确定疾病风险或恢复力的预测因素至关重要。一大一致性 与产前侮辱相比，男性更容易受到伤害。在这个提案中，我们利用我们的小鼠模型 早期产前应激（EPS）以检查性别特异性胎盘转录调控。在我们的 EPS 模型中， 男性（而非女性）后代的应激敏感性增加，包括 HPA 应激轴增加 活动、断奶后生长减少和下丘脑线粒体功能障碍。性别差异 胎盘功能可能会向发育中的胎儿大脑产生性别特异性的经胎盘信号。性别 胎盘的差异始于性染色体。通过对母体进行全基因组筛选 压力，我们通过以下方法确定了 X 连锁基因 OGT 是男性特异性压力表型的因果因素 它对组蛋白转录抑制标记 H3K27me3 的调节。该提案采用了创新的 确定女性胎盘能够限制转录的机制的方法 对环境中压力的反应，而男性则不然，从而使男性发育中的大脑处于更大的状态 产前风险。发育中的大脑接收到的经胎盘信号似乎与能量有关 可用性和影响代谢和线粒体编程。具有关键转化意义的是，我们有 还发现人类胎盘组织中的胎儿性别可以预测相同的生化和分子结果。 因此，我们的建议将侧重于定义 H3K27me3 在发育风险中的因果重要性 对压力反应的变化，识别这些变化产生的性别特异性经胎盘信号 使用离体灌注来研究胎盘功能，并确定细胞区室和机制 这些变化促进下丘脑线粒体重编程和 EPS 表型。