RESEARCH PROJECT I: TEAD4 Orchestration of Trophoblast Development

摘要 滋养层细胞系构建胎盘的功能单位，对胎盘的锚定很重要 从胚胎到母亲，滋养层细胞谱系的发展始于 滋养外胚层(TE)，在着床前哺乳动物中指定的最早的两种细胞谱系之一 发展。对小鼠的基因敲除研究表明，TEAD4是包含 转录因子是TE特异性转录程序的主协调者。TEAD4-空鼠标 胚胎不成熟到囊胚期，缺乏滋养层干细胞(TSCs)的特异性表达 各种因素。为了了解滋养层细胞中TEAD4的功能，通过全基因组分析，我们确定了直接 靶基因TEAD4在小鼠TSC中的表达，发现TEAD4是维持多种mTSC-1表达所必需的。 特定的基因。然而，TEAD4建立和维持TE/TSC特异性的分子机制 人们对转录程序知之甚少。此外，我们对功能重要性的理解 TEAD4在包括人类在内的其他哺乳动物的滋养层发育方面尚处于初级阶段。 因此，这项提议的目标是测试TEAD4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和这种依赖TEAD4的转录机制是保守的 这一事件发生在包括人类在内的多种哺乳动物物种中。我们将在两种啮齿动物的TSC中定义TEAD4的全球目标 和人类滋养层祖细胞；我们将识别TEAD4增强的表观遗传学机制 滋养层染色质。此外，我们还将测试新的TEAD4相关机制是否平衡自我 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.