Stem cell epigenetics in uterine fibroids

项目摘要 子宫肌瘤(又称肌瘤)是女性生殖道最常见的肿瘤。 一些估计表明，多达75%的美国妇女患有子宫肌瘤，这取决于种族和 种族问题。由于非裔美国女性年龄在2-3岁之间，所以子宫肌瘤的发病率差异很大。 更有可能发生肌瘤，通常起病更早，症状更严重。这些肿瘤 可能会非常痛苦，也是美国子宫切除术的主要原因。尽管医疗保健负担 由子宫肌瘤引起，其病因和病理生理尚不清楚。绝大多数的子宫肌瘤 有MED12基因突变或过表达高迁移率族AT挂钩 (HMGA)1/2转录因子，但分子机制被破坏而导致肿瘤 发展或增长是未知的。肌瘤的另一个众所周知的特征是，它们大多是 克隆性，表示每个肿瘤的单个起源细胞。我们最重要的假设是，绝大多数 子宫肌瘤是从肌层干/祖细胞发展而来的，这些细胞已经变得不受任何一种 MED12突变或HMGA1/2过表达。使用SUSD2作为标记，我们对一个种群进行了丰富 具有人类间充质干细胞所有特征的血管周围肌层细胞 子宫肌瘤和肌瘤标本。血管周围壁龛是间充质干细胞最常见的部位。 许多组织中的细胞。我们有令人信服的证据表明染色质的区划在 子宫肌瘤与正常子宫肌层相比，这导致干细胞同源转化为 一种更具颈性的表型。我们建议确定子宫肌层和肌层的表观遗传图景 肌瘤干细胞影响干细胞的区间化。一旦了解了这些机制，我们 将更好地理解关键路径的中断如何影响他们的行为，最终目标是 确定治疗干预的目标。

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.