RESEARCH PROJECT II: SATB Regulation of the Trophoblast Stem Cell State

项目摘要/摘要(研究项目II) 滋养层细胞谱系在胚胎发育早期通过一种复杂的转录相互作用而产生。 以及控制关键信号通路的表观遗传调节因子。滋养层干细胞(TS)具有 自我更新和分化为特化滋养层细胞群，是建立和 维持妊娠。然而，表观遗传修饰，以及转录的层级 调节因子决定滋养层细胞的谱系，维持滋养层细胞的干细胞状态，并调节 人们对多系分化知之甚少。我们已经鉴定出两种相关蛋白质，特别是富含AT的蛋白质 序列结合蛋白1(SATB1)和SATB2，可作为染色质组织者和转录 调节剂有助于TS细胞的维持和扩增以及对滋养层细胞的抑制 差异化。SATB蛋白被认为在控制滋养层细胞的调控网络中发挥关键作用 发展。在本研究项目中，提出了三个具体目标：1)调查SATB的作用 蛋白质在决定滋养层细胞系中的作用；2)确定SATB蛋白在 控制TS细胞干细胞状态的调节因子的等级；3)评估SATB蛋白在体内的作用 滋养层细胞发育。这项拟议的研究将利用体外啮齿动物和人类干细胞模型和 通过小鼠诱变实验，探讨SATB蛋白在调控滋养层细胞发育中的作用。基因组 转录和表观遗传修饰的广泛分析将与转录组分析相结合，以 确定SATB表达的上游调控因素和SATB行动的下游目标。这项研究 研究将揭示滋养层干细胞调节的新特性，并扩大我们对 与早期妊娠丢失相关的疾病。

PROJECT SUMMARY/ABSTRACT (RESEARCH PROJECT II) The trophoblast lineage arises early in embryonic development through a complex interaction of transcriptional and epigenetic regulators controlling key signaling pathways. Trophoblast stem (TS) cells possess the capacity to self-renew and differentiate into specialized trophoblast cell populations required for the establishment and maintenance of pregnancy. However, the epigenetic modifications, and the hierarchy of the transcriptional regulators, which determine trophoblast lineage, maintain the trophoblast cell stem state and regulate the multilineage differentiation are poorly understood. We have identified two related proteins, special AT-rich sequence-binding protein 1 (SATB1) and SATB2, which can act as chromatin organizers and transcriptional regulators, contribute to both the maintenance and expansion of TS cells and the inhibition of trophoblast differentiation. SATB proteins are proposed to play a key role in the regulatory network controlling trophoblast development. In this research project, three specific aims are proposed: 1) to investigate the role of SATB proteins in the regulation of trophoblast lineage determination; 2) to establish the position of SATB proteins in the hierarchy of regulators controlling the TS cell stem state; 3) to evaluate the in vivo role of SATB proteins in trophoblast development. The proposed study will utilize in vitro rodent and human stem cell models and mouse mutagenesis to explore the role of SATB proteins in regulating the trophoblast development. Genome wide analysis of transcriptional and epigenetic modifications will be coupled to transcriptome analysis to identify upstream regulators of SATB expression and downstream targets of SATB action. This research investigation will reveal novel properties of trophoblast stem cell regulation and expand our understanding of the disorders associated with early pregnancy loss.