RESEARCH PROJECT I: TEAD4 Orchestration of Trophoblast Development

研究项目 I：TEAD4 滋养层发育的协调

基本信息

批准号：
8897428
负责人：
Soumen Paul
金额：
$ 27.56万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8897428
关键词：
Address Affect Biological Models CDX2 gene Cell Line Cell Lineage Cells Chromatin Data Development Embryo Epigenetic Process Equilibrium Event First Pregnancy Trimester Gene Expression Profile Gene Expression Regulation Genes Genetic Transcription Goals Human Impairment Inner Cell Mass Institutes Knockout Mice Mediating Modification Molecular Mothers Mus Pattern Placenta Population Rattus Reproduction Rodent Specific qualifier value Staging Stem Cell Development Stem cells Testing Tissues abstracting blastocyst cell type chromatin immunoprecipitation cytotrophoblast deep sequencing genome-wide histone modification human stem cells infancy knockout gene member mouse model natural Blastocyst Implantation novel placental mammal preimplantation progenitor programs selective expression self-renewal stem stem cell population transcription factor trophoblast

项目摘要

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.

抽象的滋养层细胞谱系构建胎盘的功能单位，对于胎盘的锚定很重要从胚胎到母亲，滋养层细胞谱系的发育始于滋养外胚层 (TE)，哺乳动物着床前指定的前两个细胞谱系之一发展。小鼠基因敲除研究表明，TEAD4 是含有 TEA 结构域的成员转录因子是 TE 特定转录程序的主要协调器。 TEAD4 缺失小鼠胚胎未成熟至囊胚期且缺乏滋养层干细胞 (TSC) 特异性表达因素。为了了解滋养层细胞中的 TEAD4 功能，通过全基因组分析，我们确定了直接小鼠 TSC 中 TEAD4 的靶标，发现 TEAD4 是维持多种 mTSC 表达所必需的特定基因。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物种的滋养层发育中还处于起步阶段。因此，该提案的目标是检验 TEAD4 选择性协调 TSC/滋养层的假设祖细胞特异性转录程序和这种 TEAD4 依赖性转录机制是保守的包括人类在内的多种哺乳动物物种中的事件。我们将在两个啮齿动物 TSC 中定义 TEAD4 的全球目标和人类滋养层祖细胞；我们将确定 TEAD4 增强的表观遗传机制滋养层染色质。此外，我们还将测试新颖的 TEAD4 相关机制是否平衡自我 TSC 的更新与分化。