RESEARCH PROJECT III: Histone H3K9 Methylation and Trophoblast Lineage Developmen

研究项目 III：组蛋白 H3K9 甲基化和滋养层谱系发育

• 批准号: 9341564
• 负责人: MICHAEL J SOARES
• 金额: $ 8.05万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9341564
• 关键词: Affect; Cell model; Cell physiology; Cells; Competence; Development; Disease; Embryo; Embryonic Development; Engineering; Environment; Epigenetic Process; Event; Female; Fetal Growth; Gatekeeping; Genes; Genetic; Growth; Hemochorial Placental Development; Histones; In Vitro; Investigation; Lead; Link; Methylation; Modeling; Modification; Molecular; Placentation; Pregnancy; Pregnancy loss; Process; Rattus; Recurrence; Regulation; Research; Research Project Grants; Role; Stem cells; Transferase; abstracting; chromatin modification; failure Implantation; histone modification; in vivo; innovation; postnatal; reproductive tract; self-renewal; stem; stem cell division; transcription factor; trophoblast

PROJECT SUMMARY/ABSTRACT (RESEARCH PROJECT III) The establishment of pregnancy requires acquisition of key competencies within the embryo and female reproductive tract. Central to embryo competence is development of the trophoblast lineage, which represents the initial differentiation event during embryogenesis. Trophoblast cells are situated at the embryo-uterine interface and contribute fundamentally to the growth and survival of the embryo in the female reproductive tract. These vital tasks are accomplished through appropriate expansion of trophoblast stem (TS) cells and their accrual of specializations facilitating trophoblast modification of the uterine environment. Disruptions in trophoblast lineage development are associated with implantation failure, recurrent pregnancy loss, and a range of diseases affecting placentation, fetal growth, and postnatal development. Thus it is essential to understand molecular mechanisms underlying the regulation of TS cell renewal and differentiation. Transcriptional and epigenetic regulators control these fundamental processes, which are conserved across species utilizing hemochorial placentation. We have demonstrated the involvement of a defined set of histone modifications in the process of TS cell renewal and differentiation. We propose that Suv39h2, a histone H3K9 methyl transferase, and Kdm3a, a histone H3K9 demethylase, can act as a developmental switches regulating the TS cell stem state and acquisition of specialized trophoblast functions. Through chromatin modifications such as those engineered by Suv39h2 and Kdm3a networks of genes can be activated or silenced. In this project, three aims are proposed: 1) to evaluate the impact of histone H3K9 methylation machinery on TS cell renewal and differentiation; 2) to identify gene networks linked to dynamic histone H3K9 methylation changes during TS cell renewal and differentiation; 3) to elucidate transcription factor and co-regulator circuitry that impacts histone H3K9 methylation machinery. The investigation utilizes in vitro stem cell models and in vivo rat models to explore the role of histone H3K9 methylation in regulating the TS cell state. The proposed research provides an innovative approach to study TS cell regulation and to expand our understanding of early pregnancy loss.

项目摘要/摘要(研究项目III) 怀孕的确立需要获得胚胎和女性的关键能力。 生殖道。胚胎能力的核心是滋养层谱系的发展，这代表着 胚胎发生过程中的初始分化事件。滋养层细胞位于胚胎-子宫。 并从根本上促进了雌性生殖器胚胎的生长和存活 一条小路。这些重要任务是通过适当扩增滋养层干细胞和 他们所积累的特化促进了滋养细胞对子宫环境的改变。中途中断 滋养层细胞系的发育与着床失败、反复妊娠丢失和 影响胎盘、胎儿生长和出生后发育的一系列疾病。因此，至关重要的是 了解调控TS细胞更新和分化的分子机制。 转录和表观遗传调节因子控制着这些基本的过程，这些过程在 利用血绒毛胎盘的物种。我们已经证明了一组确定的组蛋白的参与 TS细胞更新和分化过程中的修饰。我们提出了Suv39h2，一个组蛋白H3K9 甲基转移酶和组蛋白H3K9去甲基酶KDM3A可作为发育开关调节 TS细胞的干细胞状态和特化滋养层功能的获得。通过染色质修饰 例如那些由Suv39h2和KDM3A设计的基因网络可以被激活或沉默。在这 1)评估组蛋白H3K9甲基化机制对TS细胞的影响 更新和分化；2)确定与组蛋白H3K9甲基化动态变化相关的基因网络 在TS细胞更新和分化过程中；3)阐明转录因子和辅助调节电路 影响组蛋白H3K9甲基化机制。该研究利用体外干细胞模型和体内大鼠 探索组蛋白H3K9甲基化在调节TS细胞状态中的作用。拟议的研究 提供了一种创新的方法来研究TS细胞的调节，并扩大了我们对早期 妊娠丢失。