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Epigenetic mechanisms of tumor formation in Beckwith-wiedemann Syndrome

Beckwith-wiedemann 综合征肿瘤形成的表观遗传机制

基本信息

批准号：
9813688
负责人：
NORA I ENGEL
金额：
$ 7.93万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9813688
关键词：
3-Dimensional Address Affect Beckwith-Wiedemann Syndrome Binding Sites Biological Assay CCCTC-binding factor CDKN1C gene CRISPR/Cas technology Cell Cycle Cell Line Cells Chimeric Proteins Chromatin Chromosomes Chronology DNA Methylation DNA Sequence DNA Sequence Alteration Data Development Dimensions Disease Engineering Enhancers Epigenetic Process Event Exhibits Fetal Macrosomia Fibroblasts Future Gene Expression Genes Genetic Transcription Growth Guide RNA Health Human Human Cell Line Individual Ligation Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Maps Medical Methylation Modification Molecular Conformation Mus Mutation Normal Cell Nucleic Acid Regulatory Sequences Online Mendelian Inheritance In Man Patients Phenotype Positioning Attribute Predisposition Publishing Regulatory Element Resolution Risk Role Site Syndrome Technology Testing Therapeutic Time Series Analysis Untranslated RNA carcinogenesis cell growth chromatin immunoprecipitation chromosome conformation capture comparative demethylation design epigenetic therapy epigenomics experience experimental study genome-wide high risk imprint inhibitor/antagonist insight new technology next generation novel profiles in patients promoter targeted treatment tumor

项目摘要

Beckwith-Wiedeman Syndrome (BWS) is a fetal overgrowth disorder which confers high risk for pediatric cancers. Loss of DNA methylation (LOM) in a key regulatory region of the KCNQ1 domain resulting in silencing of a critical cell cycle inhibitor, CDKN1C, occurs in a large group of patients. However, it is unknown how methylation is disrupted, how it affects other chromatin features and how it leads to tumor development. Thus, BWS provides a useful paradigm for addressing epigenetic dysregulation in cancer and offers an opportunity to test novel epigenetic therapeutic strategies. We will perform conformational, epigenetic and expression studies to determine the status of known promoters, enhancers and insulators and to identify novel regulatory sequences in the human KCNQ1 domain. We will also perform comparative analyses between normal fibroblasts and cells from BWS patients exhibiting LOM with co-occurring deletions. These comparisons will elucidate how LOM affects expression of critical genes in carcinogenesis and explain how the sequences spanned by patient deletions affect conformation and DNA methylation. We will engineer similar deletions in normal fibroblasts and epigenetically engineer normal cells to demethylate the DNA sequences affected in BWS. In addition, we will exploit epigenetic fusion proteins to rescue the epigenetic and transcriptional profiles of the patient cells. Because current epigenetic therapies act in a genome-wide manner, successful modification of specific loci with epigenetic editors portends a highly targeted therapy applicable to any cancer with deregulated gene expression.

Beckwith-Wiedeman综合征（BWS）是一种胎儿过度生长障碍，癌的KCNQ 1结构域关键调控区的DNA甲基化（LOM）缺失导致沉默一个关键的细胞周期抑制剂，CDKN 1C，发生在一个大的患者群体。然而，不知道如何甲基化被破坏，它如何影响其他染色质特征以及它如何导致肿瘤发展。因此，在本发明中， BWS为解决癌症中的表观遗传失调提供了一个有用的范例，并提供了一个有机会测试新的表观遗传治疗策略。我们将进行构象，表观遗传和表达研究，以确定已知的启动子、增强子和绝缘子的状态，并鉴定新的人KCNQ 1结构域中的调节序列。我们还将进行比较分析，正常的成纤维细胞和来自BWS患者的表现出具有共发生缺失的LOM的细胞。这些比较将阐明LOM如何影响癌发生中关键基因的表达，并解释患者缺失跨越的序列影响构象和DNA甲基化。我们将设计类似的正常成纤维细胞中的缺失和表观遗传工程正常细胞去甲基化DNA序列受BWS影响。此外，我们将利用表观遗传融合蛋白来拯救表观遗传和患者细胞的转录谱。因为目前的表观遗传疗法是以全基因组的方式起作用的，用表观遗传编辑器对特定基因座的成功修饰预示着一种高度靶向的治疗方法，任何基因表达失调的癌症