Role of Long-Range Chromatin Interactions in Genetic Disease

长程染色质相互作用在遗传性疾病中的作用

• 批准号: 8111308
• 负责人: ANDREW R HOFFMAN
• 金额: $ 35.09万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111308
• 关键词: 22q11; Affect; Biological Assay; Candidate Disease Gene; Cardiac; Cataloging; Catalogs; Cell Line; Cells; Chromatin; Chromosomal Rearrangement; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 8; Complex; DNA; Development; Disease; Fluorescent in Situ Hybridization; Genes; Genetic; Genetic Risk; Genomics; Hereditary Disease; Human; Individual; Knockout Mice; Learning; Malignant Neoplasms; Medical Genetics; Methodology; Molecular; Molecular Conformation; Patients; Phenotype; Publishing; RNA; Resolution; Role; Sampling; Schizophrenia; Syndrome; Testing; Variant; Work; cancer genetics; combinatorial; gene interaction; genetic risk factor; high risk; novel; public health relevance

DESCRIPTION (provided by applicant): A central paradigm of medical genetics is that the phenotype of a deletion syndrome results from the disruption of the deleted genes themselves. In direct contradistinction to this dogma, we propose that genetic diseases can be caused or modified by changes in physical, long-range interactions that normally occur between loci that are now deleted and genes that are far from the deleted region when plotted on a linear genetic map. In contrast to focusing on singe deletion-candidate gene interaction, though, we propose that a network of co- regulated genes physically co-localizes, and that phenotypic variation results from the combinatorial disruption of different spokes of this chromatin hub in different individuals. Since deletion syndromes are often characterized by multiple phenotypes, we will test our hypothesis on the most common genomic deletion disorder, deletion of human 22q11 (del22q11), which is characterized by remarkable phenotypic variation. del22q11 may be the most common genetic risk factor for schizophrenia. We have identified a hub of 13 genes on 8 chromosomes that physically interacts with 22q11. We will study DNA and RNA samples from fully phenotyped patients who harbor the deletion, as well as cell lines from normal and affected patients. 1) Using the Associated Chromosome Trap assay, our recently published novel methodology for discovering long-range chromatin interactions, we will identify all genes that physically interact with the commonly deleted region of 22q11. 2) We will confirm that these interactions occur in healthy individuals using fluorescent in situ hybridization and the high-resolution molecular assay chromosome conformation capture. 3) We can then use this catalog of associated genes to examine their potential roles in disease manifestation. 4) We will use knock-out mice to confirm the role of the genes in this hub in cardiac development and disease. This proposal is high-risk because we aim to focus on the physical network itself, rather than the high-yield disease-causing genes that compose those networks. The impact of this hypothesis will extend beyond genetic syndromes to chromosomal rearrangements in cancers, and it will uncover and explain genetic risks for complex diseases. PUBLIC HEALTH RELEVANCE: Genes on different chromosomes may physically interact with each other and affect the way those genes work in a cell. In some cancers and genetic diseases, these long range associations between genes are lost because a part of a chromosome becomes deleted. By examining the network of long range interactions among genes, we will learn how diseases are caused by the change in the expression of many genes which become abnormally regulated when the interactions are lost.

描述（由申请人提供）：医学遗传学的中心范式是缺失综合征的表型是由于缺失基因本身的中断而导致的。与这种教条直接矛盾，我们建议遗传疾病可以通过通常在基因座之间被删除的基因座和远离删除区域的基因之间发生的物理，长期相互作用而引起或修改。不过，与关注单次缩合基因相互作用相反，我们提出，共同调节基因的网络在物理上共定位，并且表型变异是由于该染色质枢纽在不同个体中的不同辐条的组合破坏。由于缺失综合征通常以多种表型为特征，因此我们将测试我们对最常见的基因组缺失障碍，人类22q11（DEL22Q11）的假设，其特征在于显着的表型变化。 DEL22Q11可能是精神分裂症最常见的遗传危险因素。我们已经确定了一个与22q11物理相互作用的8个染色体上的13个基因的枢纽。我们将研究含有缺失的完全表型患者的DNA和RNA样品，以及正常患者和受影响患者的细胞系。 1）使用相关的染色体陷阱测定，我们最近发表的用于发现远程染色质相互作用的新方法，我们将确定所有与22q11的常见删除区域物理相互作用的基因。 2）我们将使用荧光原位杂交和高分辨率分子测定染色体构象捕获这些相互作用发生在健康个体中。 3）然后，我们可以使用这种相关基因的目录来检查其在疾病表现中的潜在作用。 4）我们将使用敲除小鼠来确认该基因在该枢纽心脏发育和疾病中的作用。该建议是高风险的，因为我们旨在专注于物理网络本身，而不是组成这些网络的高产性疾病基因。该假设的影响将延伸到癌症重排的遗传综合症之外，并将发现并解释复杂疾病的遗传风险。 公共卫生相关性：关于不同染色体的基因可能会在物理上相互作用，并影响这些基因在细胞中的工作方式。在某些癌症和遗传疾病中，由于染色体的一部分被删除，因此基因之间的这些远距离关联丢失了。通过检查基因之间的远距离相互作用的网络，我们将了解疾病是如何由许多基因表达的变化引起的，这些基因的表达变化在丧失相互作用时会异常受到调节。