Integrative Genomewide Analyses of HMGA2 Impact on Uterine Leiomyomas

子宫肌瘤(LM)，也称为子宫肌瘤，是子宫的良性平滑肌瘤 以广泛的细胞改变和细胞外基质(ECM)僵硬为特征。令人震惊的是，几乎 75%的女性在有生之年会患上某种形式的子宫肌瘤，其中一些人会经历显著的 症状。目前治疗LM的药物有非靶向的副作用，限制了它们的长期使用；外科手术 选择是唯一的最终治疗方法。因此，LM是一个主要的妇科保健问题，其 每年的治疗费用高达数十亿美元。不幸的是，LM背后的分子机制 肿瘤的发生和发展还知之甚少，这对癌症的发生和发展构成了重大障碍。 开发新的治疗方案。拟议的研究具有非常重要的意义，因为它们将填补 了解这种主要的妇科疾病，确定推动LM形成的机制以及 新的LM疗法的潜在靶点。尽管雌激素和孕激素信号和转化生长因子β信号转导 与LM有牵连，对LM潜在驱动因素突变的搜索导致了对 编码调节转录和3D染色质拓扑的两种主要蛋白质。过度表达通过 染色质结合蛋白高迁移率族蛋白HMGA2基因的染色体易位 (HMGA2-ra)和转录介质复合体亚单位MED12基因突变(mut-MED12)。 在Lm中被鉴定为相互排斥的驱动突变。他们加在一起贡献了几乎85%的LM。 以前的细胞遗传学、IHC、分子和全基因组测序研究清楚地确定了 HMGA2过表达在肌瘤发病机制中的作用在这项提案中，我们利用了之前的这些观察结果， 假设HMGA2的过度表达改变了它与染色质的联系，从而改变了表观遗传学 签名和强烈影响3D染色质拓扑，与正常相比，它改变了基因表达 子宫肌层组织。为了验证我们的假设，我们将追求以下两个具体目标。具体目标1，我们 将定义HMGA2-ra LM中的cstrome、转录组和表观基因组。在具体目标2中，我们将定义 HMGA2-ra Lm的染色体三维拓扑结构我们将使用最先进的全基因组技术和 生物信息学分析来实现这些目标。一旦完成，拟议的研究将促进我们的知识 这一影响世界一半人口的妇科高度流行的公共卫生挑战。这个 拟议的工作具有科学、翻译和临床意义，因为这些研究将建立 合理的临床前框架，以评估现有的治疗方法并开发针对LM、a的新疗法 重大妇科疾病。

Uterine leiomyoma (LM), also known as uterine fibroids, are benign, smooth muscle tumors of the uterus characterized by extensive cellular alteration and stiffness of the extracellular matrix (ECM). Alarmingly, almost 75% of all women will develop some form of fibroids in their lifetimes, with some experiencing significant symptoms. Current medical treatments for LM have off-target side effects that limit their long-term use; surgical options are the only definitive treatment. Consequently, LM is a major gynecologic healthcare problem, and its treatment costs billions of dollars annually. Unfortunately, the molecular mechanisms underlying LM tumorigenesis and progression are poorly understood, and this has posed a significant barrier to the development of new treatment options. The proposed studies are highly significant because they will fill a gap in knowledge about this major gynecologic disease, identifying the mechanisms that drive LM formation as well as potential targets for new LM therapies. Although estrogen and progesterone signaling and TGFβ signaling have been implicated in LM, the search for potential driver mutations in LM led to the identification of genes that encode two major proteins that regulate transcription and 3D chromatin topology. Overexpression via chromosomal translocation of the gene encoding chromatin-binding protein high mobility group protein HMGA2 (HMGA2-ra) and mutations in the transcriptional mediator complex subunit Med12 gene (mut-MED12) have been identified as mutually exclusive driver mutations in LM. They together contribute to almost 85% of all LM. Previous cytogenetic, IHC, molecular and whole genome sequencing studies clearly established a role for HMGA2 overexpression in leiomyoma pathogenesis. In this proposal, utilizing these previous observations, we hypothesize that HMGA2 overexpression alters its association with chromatin, thereby changing epigenetic signatures and strongly influencing 3D chromatin topology, which alters gene expression compared to normal myometrial tissues. To test our hypothesis, the following two specific aims will be pursued. Specific Aim 1, we will define the cistrome, transcriptome, and epigenome in HMGA2-ra LM. In Specific Aim 2, we will define chromosomal 3D-topology in HMGA2-ra LM. We will use state-of-the-art genome-wide technology and bioinformatic analysis to achieve these aims. Once completed, the proposed studies will advance our knowledge of this highly prevalent public health challenge in gynecology that affects half of the world population. The proposed work is scientifically, translationally, and clinically significant because these studies will establish a rational pre-clinical framework to assess existing treatments and develop novel therapies for targeting LM, a major gynecologic disease.