Epigenetics of uterine quiescence

子宫静止的表观遗传学

• 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
• 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

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.

conceua是位于概念和子宫内部之间的专门子宫内膜组织 怀孕期间的几个重要功能。在这样做的同时，它也必须保持“静止”，否则会冒险 损害胎盘功能或触发子宫收缩，从而过早分娩。这个静止 已经假定状态像其他任何组织一样，因为它会被压力所消除 破坏组织稳态或完整性。但是，我们最近在老鼠中的工作表明该决定是独一无二的 因为它会积极执行自己的静止，并且发生这种情况是因为decideal基质细胞（DSC） 通过H3三甲基赖氨酸的靶向启动子重音27 （H3K27me3），一个反射性组蛋白标记。这个表观遗传程序影响了一组〜800个基因，并具有 我们目前理解的影响是抑制1型免疫学和伤口愈合反应。 H3K27me3由PRC2（Polycomb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，我们建议剖析怀孕 EZH2在子宫内有条件删除的小鼠的表型，其长期目标是获得A 更深入地了解子宫静止的性质以及对怀孕的威胁的种类 判决基因沉默计划。重要的是，“ EZH2 CKO”小鼠形成植入部位，但它们是短的 居住。我们假设H3K27me3介导的DSC中的基因沉默对怀孕至关重要，因为它 面对许多潜在的组织应力，包括 在AIM 1中 接近EZH2 CKO表型，我们将确定妊娠并发症的种类 子宫EZH2缺乏症以及可能触发这些的组织应力的产生 并发症。该目标侧重于（1）植入和早期胚胎发育引起的压力， （2）后来的斑点发育，（3）全身感染和（4）直接感染。 AIM 2然后解决 EZH2 CKO CASICUA的方面已经很清楚，即其异常产生的收缩α-Smoth 肌肉肌动蛋白+肌纤维细胞。我们将确定这些细胞是否对妊娠成功构成威胁，以及 Decideal基因沉默是否通过颠覆有效的肌纤维细胞诱导来阻止其外观 TGF-β的活性，这是通过获胜而激活的生长因子。 AIM 3然后将确定Decidel基因如何 沉默计划将活化的T细胞和巨噬细胞排除在母亲界面上的能力 有助于怀孕成功。这些目标共同确定PRC2介导的基因的重要性 沉默的判决生物学，对子宫静止的性质有更深入的了解，并且 可能揭示了先前对与人类繁殖有关的妊娠的不受欢迎的威胁。