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

项目概要/摘要（研究项目II） 滋养层细胞系在胚胎发育早期通过转录因子的复杂相互作用而出现。 和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 自我更新和分化成专门的滋养层细胞群所需的建立和 维持妊娠。然而，表观遗传修饰，以及转录水平的等级， 决定滋养层细胞谱系的调节因子维持滋养层细胞干细胞状态并调节滋养层细胞的分化。 多谱系分化知之甚少。我们已经确定了两个相关的蛋白质，特别是AT丰富的 序列结合蛋白1（SATB 1）和SATB 2，可以作为染色质组织者和转录因子， 调节因子，有助于TS细胞的维持和扩增以及滋养层细胞的抑制 分化SATB蛋白被认为在控制滋养层细胞的调控网络中起关键作用 发展本研究的主要目的有三：1）探讨SATB的作用 SATB蛋白在滋养层细胞谱系决定的调节中的作用; 2）确定SATB蛋白在滋养层细胞中的位置。 控制TS细胞干细胞状态的调节剂的层次结构; 3）评估SATB蛋白在TS细胞中的体内作用， 滋养层发育拟议的研究将利用体外啮齿动物和人类干细胞模型， 小鼠突变，以探讨SATB蛋白在调节滋养细胞发育中的作用。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， 鉴定SATB表达的上游调节物和SATB作用的下游靶标。本研究 研究将揭示滋养层干细胞调节的新特性，并扩大我们对 与早孕流产有关的疾病

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.