TET2 as a novel epigenetic regulator for uterine function and fertility

TET2 作为子宫功能和生育力的新型表观遗传调节因子

基本信息

批准号：
10725828
负责人：
Xiaoqiu Wang
金额：
$ 15.2万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-08 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10725828
关键词：
Address Affect Age Aging Biological Assay Biological Process Biology Body of uterus Breeding Clinical Medicine DNA DNA Methylation Data Deacetylase Decidual Cell Reactions Diagnosis Dioxygenases Disease ESR1 gene Embryo Endometrial Endometrial Carcinoma Endometrial Stromal Cell Endometrium Epigenetic Process Epithelial Cells Epithelium Estrogens Exhibits Failure Female Fertility Future Gene Expression Genes Genetic Genetic Transcription Goals Human Impairment Implant Individual Infertility Invaded Iron LIF gene Malignant Neoplasms Mammalian Oviducts Mammals Maternal Age Molecular Mothers Mus Mutate Nuclear Receptors Ovarian Ovarian Steroid Hormone Patients Phase Phenotype Physiological Physiology Pregnancy Pregnancy Maintenance Preparation Process Production Progesterone Proliferating Protein translocation Proteins Recurrence Regulation Reproduction Reproductive Technology Research Role Sirtuins Site Stromal Cells Testing Time United States National Institutes of Health Uterine Corpus Carcinosarcoma Uterus Vagina WT1 gene Woman Work alpha ketoglutarate blastocyst chromatin modification demethylation endometriosis eutopic endometrium failure Implantation implantation in vivo meetings mouse model mutant mouse model natural Blastocyst Implantation novel oxidation response subfertility transcription factor

项目摘要

PROJECT SUMMARY Infertility and subfertility are pervasive problems in women, and failure of the endometrial adaptation to an implanting embryo is considered a significant, yet poorly understood, contributing factor. Ten-Eleven Translocation proteins (TETs) are the iron(II)/a-ketoglutarate (Fe(II)/a-KG)-dependent methylcytosine dioxygenases (TET1, TET2 and TET3) that confer active DNA demethylation by the iterative oxidation of 5- methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). TETs can also affect chromatin modifications and gene expression independent of enzymatic activity via interactions with other proteins including transcription factors (e.g., WT1) and epigenetic modifiers (e.g., SIN3A). Emerging evidence suggests that TET proteins may serve as key epigenetic regulators in response to ovarian steroid hormones estrogen (E2) and progesterone (P4) via their cognate nuclear receptors ESR1 and PGR in the regulation of normal uterine function. Our preliminary data in humans and mice has shown that all three TETs are expressed (Tet2>>Tet3>Tet1) in both endometrial epithelial and stromal cells, increased significantly during the window of receptivity but decreased in eutopic endometrium of endometriosis. Given that TET2 ranks among top-mutated genes in female cancers, particularly uterine corpus endometrial carcinoma (UCEC) and uterine carcinosarcoma (UCS), we have generated uterine Tet2-deleted female mice, PgrCre/+Tet2f/f (Tet2d/d). The Tet2d/d mothers were subfertile with normal ovarian and oviductal functions. Therefore, the goal of this proposal is to determine the in vivo role of Tet2 in uterine physiology using conditional Tet2 mutant mouse models. In Aim 1, we will determine the role of Tet2 in regulation of the window of receptivity. In Aim 2, we will determine the role of Tet2 in endometrial stromal cell decidualization in vivo. Completion of these aims will have defined the phenotypic roles of TET2 in the regulation of endometrial physiology, including implantation and decidualization in vivo. In addition, data generated from this mouse work will provide strong support for a future Standard NIH R01/R21 application, addressing the epigenetic mechanisms by which uterine epithelial and/or stromal TET2 regulate uterine function during pregnancy and disease states (e.g., endometriosis and endometrial cancer). Thus, the findings from this research will be important in informing human clinical medicine.

项目概要不孕不育和不孕不育是女性普遍存在的问题，子宫内膜未能适应不孕不育。植入胚胎被认为是一个重要但仍知之甚少的促成因素。十点十一点易位蛋白 (TET) 是铁 (II)/a-酮戊二酸 (Fe(II)/a-KG) 依赖性甲基胞嘧啶双加氧酶（TET1、TET2 和 TET3）通过 5- 的迭代氧化赋予 DNA 主动去甲基化作用甲基胞嘧啶 (5mC) 至 5-羟甲基胞嘧啶 (5hmC)、5-甲酰胞嘧啶 (5fC) 和 5-羧基胞嘧啶 (5caC)。 TET 还可以通过以下途径影响染色质修饰和基因表达，而与酶活性无关：与其他蛋白质的相互作用，包括转录因子（例如 WT1）和表观遗传修饰因子（例如 SIN3A）。新的证据表明，TET 蛋白可能作为卵巢反应的关键表观遗传调节因子。类固醇激素雌激素 (E2) 和孕激素 (P4) 通过其同源核受体 ESR1 和 PGR 正常子宫功能的调节。我们在人类和小鼠身上的初步数据表明，所有三种 TET 在子宫内膜上皮细胞和间质细胞中均表达（Tet2>>Tet3>Tet1），在子宫内膜异位症在位子宫内膜的容受性窗口但减少。鉴于 TET2 排名女性癌症中的顶部突变基因，特别是子宫体子宫内膜癌（UCEC）和子宫癌癌肉瘤 (UCS)，我们生成了子宫 Tet2 缺失的雌性小鼠 PgrCre/+Tet2f/f (Tet2d/d)。 Tet2d/d 母亲生育能力低下，但卵巢和输卵管功能正常。因此，本提案的目标是使用条件 Tet2 突变小鼠模型确定 Tet2 在子宫生理学中的体内作用。在目标 1 中，我们将确定 Tet2 在接受窗口调节中的作用。在目标 2 中，我们将确定角色 Tet2在体内子宫内膜基质细胞蜕膜化中的作用。完成这些目标将定义 TET2 在子宫内膜生理学调节中的表型作用，包括着床和蜕膜化体内。此外，这项小鼠工作产生的数据将为未来的标准 NIH 提供强有力的支持 R01/R21 应用，解决子宫上皮和/或基质 TET2 的表观遗传机制在怀孕和疾病状态（例如子宫内膜异位症和子宫内膜癌）期间调节子宫功能。因此，这项研究的结果对于人类临床医学具有重要意义。