Stem cell epigenetics in uterine fibroids

项目摘要 子宫肌瘤（也称为平滑肌瘤）是女性生殖道最常见的肿瘤。 一些估计表明，高达75%的美国妇女患有子宫肌瘤，这取决于种族和年龄。 种族有一个显着的差距，在发病率的肌瘤，因为非洲裔美国妇女是2-3 倍更容易发展成肌瘤，往往与早期发病和更严重的症状。这些肿瘤 可能非常痛苦，是美国直肠切除术的主要原因。尽管医疗负担 由子宫肌瘤引起，其病因学和病理生理学尚不清楚。绝大多数的子宫肌瘤 在介体复合物蛋白12（MED 12）基因中有突变或过表达高迁移率族AT钩 （HMGA）1/2转录因子，但其分子机制被破坏并导致肿瘤 发育或生长是未知的。子宫肌瘤的另一个众所周知的特点是，它们大多是 克隆，表明每个肿瘤的起源是单个细胞。我们的总体假设是， 子宫肌瘤由子宫肌层干/祖细胞发展而来， MED 1/2突变或HMGA 1/2过表达。使用SUSD 2作为标记，我们富集了一个群体， 血管周围子宫肌层细胞的所有特征的间充质干细胞从两个人 子宫肌层和纤维瘤标本。间充质干细胞最常见的生长部位是血管周围的小生境 许多组织中的细胞。我们有令人信服的证据表明，染色质区室化是改变， 子宫肌瘤与正常子宫肌层相比，这导致干细胞同源异型转化为 一个更宫颈的表型。我们建议确定子宫肌层的表观遗传景观和 纤维瘤干细胞影响干细胞中的区室化。一旦了解了这些机制，我们 将更好地了解关键途径的中断如何影响他们的行为，最终目标是 找到治疗干预的目标。

Project Summary Uterine fibroids (also known as leiomyomas) are the most common tumors in the female reproductive tract. Some estimates indicate that up to 75% of American women have uterine fibroids, depending on race and ethnicity. There is a significant disparity in the incidence of fibroids since African-American women are 2-3 times more likely to develop fibroids, often with earlier onset and greater severity of symptoms. These tumors can be very painful and are the leading cause of hysterectomies in the US. Despite the healthcare burden caused by uterine fibroids, their etiology and pathophysiology are unknown. The vast majority of fibroids either have mutations in Mediator Complex protein 12 (MED12) gene or over-express high mobility group AT hooks (HMGA)1/2 transcription factors, but the molecular mechanism that are disrupted and lead to tumor development or growth are unknown. Another well known characteristic of fibroids is that they are mostly clonal, indicating a single cell of origin for each tumor. Our overarching hypothesis is that the vast majority of uterine fibroids develop from myometrial stem/progenitor cells that have become dysregulated by either MED12 mutation or HMGA1/2 over-expression. Using SUSD2 as a marker, we have enriched for a population of perivascular myometrial cells with all the characteristics of mesenchymal stem cells from both human myometrial and fibroid specimens. The perivascular niche is the most common site for mesenchymal stem cells in many tissues. We have compelling evidence that chromatin compartmentalization is changed in uterine fibroids compared to normal myometrium, which leads to homeotic transformation of the stem cell into a more cervical phenotype. We propose to determine how the epigenetic landscape of the myometrial and fibroid stem cells affects compartmentalization in the stem cells. Once these mechanisms are understood, we will have a better understanding of how disruption of key pathways affect their behavior, with the ultimate goal of identifying targets for therapeutic intervention.