Activation of human placental hormonal expression

描述(申请人提供)：哺乳动物发育中已知的最早的步骤是从具有全潜能的胚胎干细胞形成滋养层。随后滋养层干细胞(TS)分化为胎盘合体滋养层细胞(SYNT)，建立了胎儿和母体循环系统之间的上皮界面，调节必要的营养物质交换和氧气运输。SYNT也是胎儿荷尔蒙产生的主要场所，调节母体和胎儿系统以维持成功的妊娠。在SYNT中合成的主要激素是绒毛膜生长激素(HCS)和生长激素变体(hGH-V)。这两种激素都编码在多基因人类生长激素(HGH)基因簇中，该基因簇还包括垂体生长激素基因hGH-N。我们假设，在TS向SYNT分化过程中，胎盘HCS和hGH-V基因的选择性和强健激活反映了一种明确的表观遗传修饰和染色质结构变化的进展，这些变化将这一途径与涉及垂体生长激素hGH-N激活的途径区分开来。我们进一步假设，这种发育过程反映了对SYNT分化至关重要的全球表观遗传控制，并将这一谱系与导致侵袭性滋养层细胞形成的TS派生谱系区分开来。因此，hGH簇中胎盘表达基因的选择性激活为理解基因激活机制提供了一个最佳模型，这些基因激活机制是支持TS细胞分化和定义胎盘中SYNT细胞功能的(S)。我们的建议将解决五个具体目标：i.建立小鼠TS系，模拟hGH基因在SYNT分化过程中的激活。II.确定hGH基因座上与SYNT谱系承诺和随后的HCS/hGH-V基因转录诱导相一致的结构变化。建立SYNT分化和hGH基因座激活之间的机制联系。确定SYNT中激活所需的hGH基因座的结构特征。确定胎盘特异基因激活所必需的SYNT中hGH染色质基因的高位构象。这些研究将扩大我们对胎盘基因表达和发育的理解，并扩大我们对妊娠期间影响母婴健康的相应缺陷的洞察力。公共卫生相关性：正常发育和功能正常的胎盘对妊娠至关重要。它负责母亲和胎儿之间的基本营养交换和氧气运输，是胎儿荷尔蒙产生的主要来源。这个项目将研究有关人类胎盘发育和功能的具体问题，在某些情况下，使用转基因小鼠模型。这些研究有望扩大我们对妊娠期母婴健康的理解。

DESCRIPTION (provided by applicant): The earliest known step in mammalian development is the formation of the trophoblast from the totipotential embryonic stem cell. The subsequent differentiation of the trophoblast stem cells (TS) to the placental syncytiotrophoblast (SynT) establishes the epithelial interface between fetal and maternal circulatory systems, mediating essential nutrient exchange and oxygen transport. The SynT also serves as the primary site of fetal hormone production that conditions maternal and fetal systems to sustain a successful gestation. The major hormones synthesized in the SynT are chorionic somatomammotropin (hCS) and growth hormone-variant (hGH-V). Both hormones are encoded in the multi-gene human growth hormone (hGH) gene cluster that also encompasses the pituitary growth hormone gene, hGH-N. We hypothesize that the selective and robust activation of the placental hCS and hGH-V genes during differentiation of TS to SynT reflects a defined progression of epigenetic modifications and alterations in chromatin structures that distinguish this pathway from that involved in activation of hGH-N in pituitary somatotropes. We further hypothesize that this developmental progression reflects global epigenetic controls that are fundamental to SynT differentiation and distinguish this lineage from the TS-derived lineage that leads to the formation of invasive trophoblast cells. The selective activation of the placentally-expressed genes from the hGH cluster thus presents an optimal model for understanding mechanisms of gene activation that underlie TS cell differentiation and that define function(s) of SynT cells in the placenta. Our proposal will address five Specific Aims: I. Establish mouse TS lines that model activation of the hGH locus during SynT differentiation. II. Define the structural alterations at the hGH locus that coincide with SynT-lineage commitment and the subsequent transcriptional induction of the hCS/hGH-V genes. III. Establish mechanistic linkages between SynT differentiation and hGH locus activation. IV. Identify structural features of the hGH locus required for activation in SynT. V. Define higher-order conformations at the hGH chromatin locus in SynT necessary for placenta-specific gene activation. These studies should expand our understanding of placental gene expression and development and expand our insights into the corresponding defects that impact on maternal and fetal health during gestation. PUBLIC HEALTH RELEVANCE: A normally developed and functioning placenta is critical to gestation. It is responsible for essential nutrient exchange and oxygen transport between mother and fetus and is a major source of fetal hormone production. This project will study specific questions regarding the development and function of the human placenta, in some cases using transgenic mouse models. These studies are expected expand our understanding maternal and fetal health during gestation.