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：
8743037
负责人：
Soumen Paul
金额：
$ 28.27万
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：
2014
资助国家：
美国
起止时间：
2014-07-24 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8743037
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.

抽象的滋养细胞细胞谱系构建胎盘的功能单位，对于锚固至关重要母亲的胚胎，滋养细胞细胞谱系的发展始于建立滋养剂（TE），这是植入前哺乳动物期间指定的前两个细胞谱系之一发展。小鼠的基因敲除研究表明，含有茶域的成员Tead4 转录因子是特定于TE特定转录程序的主要编排者。 tead4-null鼠标胚胎不成熟到胚泡阶段，并且缺乏特定于滋养细胞干细胞（TSC）的表达因素。为了了解滋养细胞细胞中的TEAD4功能，通过基因组广泛的分析，我们发现了直接的小鼠TSC中TEAD4的靶标，发现Tead4需要保持几个MTSC-的表达特定基因。然而，Tead4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在包括人类在内的其他哺乳动物物种的滋养细胞发展的背景下，Tead4仍处于起步阶段。因此，该提案的目的是检验以下假设：TEAD4有选择地协调TSC/Trophophotblast 祖细胞特异性转录程序和该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的全局目标和人类滋养细胞祖细胞；我们将确定Tead4增强的表观遗传机制滋养细胞染色质。此外，我们还将测试新型TEAD4相关机制是否平衡自我 TSCS的更新与差异化。