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.

蜕膜是位于孕体和子宫肌层之间的特化子宫内膜组织， 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”，否则就有风险。 危及胎盘功能或引发子宫收缩，从而导致早产。这份宁静 状态被认为与任何其他组织的状态一样，因为它会被应力消除， 破坏组织的稳态或完整性。然而，我们最近在小鼠身上的研究表明， 因为它积极地强制自己的静止，这是因为蜕膜基质细胞（DSC） 通过靶向启动子积累H3三甲基赖氨酸27转录沉默威胁沉默基因 （H3 K27 me 3），一种抑制性组蛋白标记。这种表观遗传程序影响了一组不同的~800个基因， 我们目前所理解的作用是抑制1型免疫和伤口愈合反应。 H3 K27 me 3由PRC 2（Polycomb Repressive Complex 2）产生，其主要催化亚基是H3 K27 me 3。 组蛋白甲基转移酶EZH 2（Zeste同源物2增强子）。在这里，我们建议解剖怀孕 Ezh 2在子宫内条件性缺失的小鼠的表型，其长期目标是获得 更深入地了解子宫静止的性质和通过子宫收缩减轻的对妊娠的威胁 蜕膜基因沉默程序。重要的是，“Ezh 2 cKO”小鼠形成抑制位点，但它们是短的- 居住我们假设H3 K27 me 3介导的DSCs基因沉默对妊娠至关重要，因为它 在面对许多潜在的组织应力时，以伞状方式发挥作用，以加强子宫静止，包括 感染，同种免疫反应，组织损伤，甚至胎盘发育本身。在目标1中， 最普遍地接近Ezh 2 cKO表型，我们将确定 由于子宫Ezh 2缺乏以及可能引发这些的组织应力引起 并发症本研究的重点是（1）着床和早期胚胎发育引起的应激， (2)胎盘发育后期，（3）全身性炎症，（4）直接感染。目标2然后解决一个 Ezh 2 cKO蜕膜的一个方面已经很清楚，即其异常产生的收缩性α-平滑 肌肌动蛋白+肌成纤维细胞。我们将确定这些细胞是否对怀孕成功构成威胁， 蜕膜基因沉默是否通过破坏有效的肌纤维母细胞诱导 TGF-β的活性，一种由创伤激活的生长因子。目标3将确定脱落基因如何 沉默程序将活化的T细胞和巨噬细胞从母胎界面排除的能力 有助于怀孕成功。总之，这些目标将建立PRC 2介导的基因的重要性， 在蜕膜生物学中的沉默，提供了对子宫静止的性质的更好理解， 可能揭示了以前未被认识到的与人类生殖有关的怀孕威胁。