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: 10613378
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613378
• 关键词: 3-Dimensional; AT-Hook Motifs; ATAC-seq; Affect; Architecture; Benign; Binding; 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; Medical; Molecular; Mutation; Myometrial; Operative Surgical Procedures; Pathogenesis; Pathology; Population; Process; Progesterone; Proliferating; 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; clinically significant; cost; data integration; 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.

子宫平滑肌瘤（LM），也被称为子宫肌瘤，是良性，平滑肌肿瘤的子宫 其特征在于广泛的细胞改变和细胞外基质（ECM）的硬度。令人震惊的是，几乎 75%的女性在一生中会患上某种形式的子宫肌瘤，其中一些人会经历严重的子宫肌瘤 症状目前LM的医学治疗具有脱靶副作用，限制了其长期使用;手术治疗 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 每年的治疗费用高达数十亿美元。不幸的是，LM的分子机制 肿瘤的发生和进展知之甚少，这对肿瘤的治疗构成了重大障碍。 开发新的治疗方案。拟议的研究非常重要，因为它们将填补 了解这种主要的妇科疾病，确定驱动LM形成的机制，以及 新LM疗法的潜在靶点。虽然雌激素和孕激素信号和TGFβ信号有 与LM有关，寻找LM中潜在的驱动突变导致鉴定出 编码调节转录和3D染色质拓扑结构的两种主要蛋白质。过表达通过 编码染色质结合蛋白高迁移率族蛋白HMGA 2的基因的染色体易位 HMGA 2-ra和转录介质复合物亚基Med 12基因突变（mut-MED 12）已经被证实是一种新的基因突变。 被鉴定为LM中的互斥驱动突变。它们共同贡献了几乎85%的LM。 之前的细胞遗传学、免疫组化、分子和全基因组测序研究清楚地确定了 HMGA 2过表达在子宫肌瘤发病机制中的作用在这个建议中，利用这些以前的观察，我们 假设HMGA 2过表达改变了其与染色质的结合，从而改变了表观遗传学 签名和强烈影响3D染色质拓扑结构，与正常情况相比，这会改变基因表达 子宫肌层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HMGA 2-ra LM中的顺式组、转录组和表观基因组。在具体目标2中，我们将定义 HMGA 2-ra LM中的染色体3D拓扑结构。我们将使用最先进的全基因组技术， 生物信息学分析，以实现这些目标。一旦完成，拟议的研究将促进我们的知识 妇科疾病是一个非常普遍的公共卫生挑战，影响了世界一半的人口。的 建议的工作在科学上，诊断上和临床上都很重要，因为这些研究将建立一个 合理的临床前框架，以评估现有的治疗方法，并开发针对LM的新疗法， 重大妇科疾病。