Epigenetics of uterine quiescence

子宫静止的表观遗传学

基本信息

批准号：
10293599
负责人：
Adrian Erlebacher
金额：
$ 62.18万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-08 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10293599
关键词：
Address Affect Alleles Antigens Appearance Behavior Biology Catalytic Domain Cells Complex Conceptus Decidua EZH2 gene Embryonic Development Endometrial Enhancers Epigenetic Process Epithelial Female Fetal Growth Retardation Fetus Fostering Gene Expression Gene Silencing Gene Transfer Generations Genes Goals Growth Factor Histones Homeostasis Homologous Gene Human Immune system Immunity Immunosuppression Infection Lentivirus Leukocytes Link LoxP-flanked allele Lysine Maternal-Fetal Exchange Mediating Microbe Mus Myofibroblast Natural Killer Cells Nature Phenotype Physiological Placenta Placentation Play Polycomb Positioning Attribute Pregnancy Pregnancy Complications Pregnancy Outcome Premature Birth Premature Labor Process Reproduction Risk Role Site Smooth Muscle Actin Staining Method Stress Stromal Cells T-Lymphocyte Time Tissues Transforming Growth Factor beta Uterine Contraction Uterus Vascular remodeling Work congenital infection demethylation experimental study fetal genome-wide genome-wide analysis histone methyltransferase implantation insight macrophage myometrium prevent programs promoter recruit response success systemic inflammatory response tissue stress wound wound healing

项目摘要

The decidua, the specialized endometrial tissue positioned between the conceptus and myometrium, performs several important functions during pregnancy. While doing so, it must also remain “quiescent” or else risk compromising placental function or triggering uterine contractions and thus premature delivery. This quiescent state has been assumed to be like that of any other tissue, in that it would be abrogated by stresses that disrupt tissue homeostasis or integrity. However, our recent work in mice suggests that the decidua is unique in that it actively enforces its own quiescence, and that this occurs because decidual stromal cells (DSCs) transcriptionally silence quiescence-threatening genes via targeted promoter accrual of H3 trimethyl lysine 27 (H3K27me3), a repressive histone mark. This epigenetic program impacts a diverse set of ~800 genes, with the effects we currently understand being the suppression of type 1 immunity and wound healing responses. H3K27me3 is generated by PRC2 (Polycomb Repressive Complex 2), whose primary catalytic subunit is the histone methyltransferase EZH2 (Enhancer of Zeste Homolog 2). Here, we propose to dissect the pregnancy phenotype of mice in which Ezh2 is conditionally deleted within the uterus, with the long-term goal of gaining a greater insight into the nature of uterine quiescence and the kinds of threats to pregnancy mitigated by the decidual gene silencing program. Importantly, “Ezh2 cKO” mice form implantations sites, but they are short- lived. We hypothesize that H3K27me3-mediated gene silencing in DSCs is critical to pregnancy because it acts in umbrella fashion to enforce uterine quiescence in the face of many potential tissue stresses, including infection, allo-immune responses, tissue damage, and even placental development itself. In Aim 1, which approaches the Ezh2 cKO phenotype most generally, we will identify the kinds of pregnancy complications that result from uterine Ezh2 deficiency, as well as the kinds of tissue stresses that might trigger these complications. The Aim focuses on the stresses caused by (1) implantation and early embryonic development, (2) later placental development, (3) systemic inflammation, and (4) direct infection. Aim 2 then addresses an aspect of the Ezh2 cKO decidua that is already clear, namely its aberrant generation of contractile α-smooth muscle actin+ myofibroblasts. We will determine whether these cells pose a threat to pregnancy success, and whether the decidual gene silencing prevents their appearance by subverting the potent myofibroblast-inducing activity of TGF-β, a growth factor activated by wounding. Aim 3 will then determine how the decidual gene silencing program's ability to exclude activated T cells and macrophages from the maternal-fetal interface contributes to pregnancy success. Together, these aims will establish the importance of PRC2-mediated gene silencing in decidual biology, provide a greater understanding of the nature of uterine quiescence, and potentially reveal previously unappreciated threats to pregnancy relevant to human reproduction.

蜕膜是位于孕体和子宫肌层之间的特殊子宫内膜组织，执行在怀孕期间的几个重要功能中，它也必须保持“静止”，否则就有风险。损害胎盘功能或引发子宫收缩，从而导致早产。假设状态与任何其他组织的状态一样，因为它会被以下应力所消除：然而，我们最近对小鼠的研究表明，蜕膜是独特的。因为它主动强制自己处于静止状态，这是因为蜕膜基质细胞（DSC）通过 H3 三甲基赖氨酸 27 的靶向启动子累积，转录沉默威胁静止的基因 (H3K27me3)，一种抑制性组蛋白标记，该表观遗传程序影响约 800 个不同的基因。我们目前了解的影响是抑制 1 型免疫和伤口愈合反应。 H3K27me3 由 PRC2（多梳抑制复合物 2）产生，其主要催化亚基是组蛋白甲基转移酶 EZH2（Zeste 同源物 2 的增强子）在这里，我们建议剖析妊娠。 Ezh2 在子宫内被条件性删除的小鼠表型，长期目标是获得更深入地了解子宫静止的本质以及通过子宫静止减轻的妊娠威胁类型重要的是，“Ezh2 cKO”小鼠形成植入位点，但它们是短的。我们认为 DSC 中 H3K27me3 介导的基因沉默对于妊娠至关重要，因为它在面对许多潜在的组织压力时，以保护伞的方式发挥作用，以强制子宫静止，包括感染、同种免疫反应、组织损伤，甚至胎盘发育本身，这在目标 1 中。最普遍地接近 Ezh2 cKO 表型，我们将确定哪些类型的妊娠并发症由子宫 Ezh2 缺陷以及可能引发这些的组织压力引起目标集中于以下因素引起的压力：(1) 着床和早期胚胎发育， (2) 后期胎盘发育，(3) 全身炎症，(4) 直接感染。 Ezh2 cKO 蜕膜的一个方面已经很清楚了，即它的收缩性 α-smooth 的异常生成我们将确定这些细胞是否对妊娠成功构成威胁，以及蜕膜基因沉默是否通过破坏有效的肌成纤维细胞诱导作用来防止它们的出现 TGF-β（一种由受伤激活的生长因子）的活性将决定蜕膜基因的作用。沉默程序能够将活化的 T 细胞和巨噬细胞排除在母胎界面之外这些目标共同有助于妊娠成功。蜕膜生物学的沉默，提供对子宫静止本质的更深入的了解，以及可能揭示以前未被认识到的与人类生殖相关的怀孕威胁。