RESEARCH PROJECT I: TEAD4 Orchestration of Trophoblast Development

摘要 滋养层细胞谱系构建胎盘的功能单位，并且对于胎盘的锚定是重要的。 滋养层细胞谱系的发育始于胚胎的发育， 滋养外胚层（TE），在植入前哺乳动物中指定的前两个细胞谱系之一， 发展小鼠中的基因敲除研究表明，TEAD 4，一个含有TEA结构域的成员， 转录因子是TE特异性转录程序的主要协调者。TEAD 4基因敲除小鼠 胚胎不能成熟到胚泡阶段，并且缺乏滋养层干细胞（TSCs）特异性的表达。 因素为了了解TEAD 4在滋养层细胞中的功能，通过全基因组分析，我们鉴定了直接的TEAD 4基因。 TEAD 4在小鼠TSC中的靶点，并发现TEAD 4是维持几种mTSC表达所必需的。 特定基因然而，TEAD 4通过其建立和维持TE/TSC特异性的分子机制， 转录程序知之甚少。此外，我们对功能重要性的理解 TEAD 4在其他哺乳动物物种（包括人类）滋养层发育中的作用尚处于起步阶段。 因此，该提议的目标是检验TEAD 4选择性地协调TSC/滋养层细胞的假设。 祖细胞特异性转录程序，这种TEAD 4依赖性转录机制是保守的 在包括人类在内的多种哺乳动物物种中发生。我们将在两种啮齿动物TSC中定义TEAD 4的全局靶标 和人类滋养层祖细胞;我们将确定TEAD 4增强的表观遗传机制， 滋养层染色质此外，我们还将测试新的TEAD 4相关机制是否能平衡自我调节， TSCs的更新与分化。

Abstract Trophoblast cell lineages build the functional units of the placenta and are important for the anchorage of the embryo to the mother, The development of trophoblast cell lineages starts with the establishment of the trophectoderm (TE), one of the first two cell lineages that are specified during preimplantation mammalian development. Gene knockout studies in mice showed that TEAD4, a member of TEA-domain containing transcription factors, is the master orchestrator of the TE-specific transcriptional program. TEAD4-null mouse embryos do not mature to the blastocyst stage and lack expression of trophoblast stem cells (TSCs) specific factors. To understand TEAD4 function in trophoblast cells, through genome wide analyses we identified direct targets of TEAD4 in mouse TSCs and found that TEAD4 is required to maintain expression of several mTSC- specific genes. However, molecular mechanism, by which TEAD4 establishes and maintains a TE/TSC-specific transcriptional program are poorly understood. Furthermore, our understanding about the functional importance of TEAD4 in the context of trophoblast development in other mammalian species including human is at its infancy. Thus, the goal of this proposal is to test the hypothesis that TEAD4 selectively orchestrates a TSC/trophoblast progenitor cell-specific transcriptional program and this TEAD4-dependent transcriptional mechanism is conserved event in multiple mammalian species including human. We will define global targets of TEAD4 in both rodent TSCs and human trophoblast progenitors; we will identify epigenetic mechanisms that are augmented by TEAD4 within trophoblast chromatin. In addition, we will also test whether novel TEAD4-associated mechanisms balances self- renewal vs. differentiation of TSCs.