Integrative Genomewide Analyses of HMGA2 Impact on Uterine Leiomyomas

HMGA2 对子宫平滑肌瘤影响的综合全基因组分析

• 批准号: 10153844
• 负责人: DEBABRATA CHAKRAVARTI
• 金额: $ 37.41万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153844
• 关键词: 3-Dimensional; AT-Hook Motifs; ATAC-seq; Address; Affect; Architecture; Benign; Binding Proteins; Bioinformatics; Biological Assay; Cells; ChIP-seq; Chromatin; Chromatin Loop; Chromatin Structure; Chromosomal translocation; Complex; Cytogenetics; DNA Binding; Data; Data Analyses; Data Set; Development; Disease; Enhancers; Epigenetic Process; Estrogens; Extracellular Matrix; Female Genital Diseases; Fibroid Tumor; Fibrosis; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genomics; Gynecologic; Gynecology; HMGA Proteins; Healthcare; Hi-C; High Mobility Group Proteins; Human; Knowledge; Leiomyoma; Link; Maps; Mediator of activation protein; Medical; Molecular; Mutation; Myometrial; Operative Surgical Procedures; Pathogenesis; Pathology; Population; Process; Progesterone; Proteins; Public Health; Publishing; RNA analysis; Research; Research Project Grants; Role; Sampling; Signal Pathway; Signal Transduction; Signaling Protein; Smooth Muscle Tumor; Symptoms; Technology; Testing; Tissues; Transforming Growth Factor beta; Treatment Cost; Uterine Fibroids; Uterine Neoplasms; Uterus; Woman; Work; base; clinically significant; cost; driver mutation; epigenome; epigenomics; experience; experimental study; gene translocation; genome sequencing; genome-wide; genome-wide analysis; human disease; human tissue; innovation; new therapeutic target; novel; overexpression; pre-clinical; promoter; side effect; transcriptome; transcriptome sequencing; tumorigenesis; whole genome

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.

子宫肌瘤 (LM)，也称为子宫肌瘤，是子宫良性平滑肌肿瘤 其特征是广泛的细胞改变和细胞外基质（ECM）的僵硬。令人震惊的是，几乎 75% 的女性在一生中会出现某种形式的肌瘤，其中一些女性会出现严重的肌瘤 症状。目前针对 LM 的药物治疗存在脱靶副作用，限制了其长期使用；外科 选择是唯一确定的治疗方法。因此，LM 是一个主要的妇科保健问题，其 每年的治疗费用达数十亿美元。不幸的是，LM 的分子机制 人们对肿瘤的发生和进展知之甚少，这对肿瘤的发生和进展构成了重大障碍。 开发新的治疗方案。拟议的研究非常重要，因为它们将填补以下方面的空白： 关于这一主要妇科疾病的知识，确定驱动 LM 形成的机制以及 新的 LM 疗法的潜在目标。尽管雌激素和孕激素信号传导以及 TGFβ 信号传导已 由于与 LM 有关，对 LM 潜在驱动突变的搜索导致了以下基因的鉴定： 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 编码染色质结合蛋白高迁移率族蛋白 HMGA2 的基因的染色体易位 (HMGA2-ra) 和转录介导复合体亚基 Med12 基因 (mut-MED12) 的突变已被 被确定为 LM 中相互排斥的驱动突变。它们合计占所有 LM 的近 85%。 先前的细胞遗传学、IHC、分子和全基因组测序研究明确确立了 HMGA2 过度表达在平滑肌瘤发病机制中的作用。在本提案中，利用这些先前的观察结果，我们 假设 HMGA2 过度表达改变了其与染色质的关联，从而改变了表观遗传 特征并强烈影响 3D 染色质拓扑，与正常相比，这改变了基因表达 子宫肌组织。为了检验我们的假设，将追求以下两个具体目标。具体目标1，我们 将定义 HMGA2-ra LM 中的顺反组、转录组和表观基因组。在具体目标 2 中，我们将定义 HMGA2-ra LM 中的染色体 3D 拓扑。我们将使用最先进的全基因组技术 生物信息分析来实现这些目标。一旦完成，拟议的研究将增进我们的知识 影响世界一半人口的妇科领域非常普遍的公共卫生挑战。这 拟议的工作具有科学、转化和临床意义，因为这些研究将建立一个 合理的临床前框架来评估现有治疗方法并开发针对 LM 的新疗法， 主要妇科疾病。