Long noncoding RNA expressing genomic element that control antibody diversification and chromosomal integrity in B cells

表达控制 B 细胞抗体多样化和染色体完整性的基因组元件的长非编码 RNA

• 批准号: 10303057
• 负责人: Uttiya Basu
• 金额: $ 47.94万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-07 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303057
• 关键词: 3-Dimensional; Accidents; Antibodies; Antibody Diversity; Antigens; B lymphoid malignancy; B-Cell Development; B-Lymphocytes; Bioinformatics; Biological Models; Biological Process; Cancer Etiology; Cell Line; Cell Proliferation; ChIP-seq; Chromatin; Chromosomal Rearrangement; Chromosomal translocation; Complex; Control Locus; DNA; DNA Binding; DNA Sequence; DNA Sequence Alteration; Data; Defect; Detection; Development; Distal; Distant; Elements; Enhancers; Evaluation; Event; Exonuclease; Failure; Frequencies; Gene Expression; Genes; Genetic Enhancer Element; Genetic Recombination; Genetic Transcription; Genome; Genomic Instability; Genomics; Heavy-Chain Immunoglobulins; Hi-C; IGH@ gene cluster; Immune system; Immunoglobulin Class Switching; Immunoglobulin Genes; Immunoglobulin Somatic Hypermutation; Immunoglobulin Switch Recombination; Investigation; Knockout Mice; Lead; Libraries; Location; Malignant Neoplasms; Mediating; Mediator of activation protein; Molecular; Mutagenesis; Mutate; Mutation; Nucleic Acid Regulatory Sequences; Oncogenic; Process; RNA; RNA Degradation; RNA Processing; Regulation; Regulator Genes; Regulatory Element; Reporting; Role; Structure of germinal center of lymph node; Transcript; Transcriptional Regulation; Untranslated RNA; base; c-myc Genes; cis acting element; combat; exosome; experimental study; genome integrity; genomic locus; immunoglobulin structure; in vivo; mammalian genome; mouse genome; mouse model; novel; prevent; promoter; protein complex; transcription factor; transcriptomics

PROJECT SUMMARY/ ABSTRACT It is becoming increasingly evident that the majority of the mammalian genome has the potential to express non-coding RNAs (ncRNAs). However, the functionality and mechanism(s) of regulation of these ncRNAs are just beginning to be explored. One challenge that biologists encounter is the detection of these ncRNAs, which often tend to be transcriptionally tightly controlled and rapidly degraded. We have recently identified a long noncoding (lnc) RNA expressing locus, known as lncRNA-CSR, that regulates DNA rearrangments in the Immunoglobulin heavy chain (IgH) locus of B cells. Using mouse model systems that lack lncRNA processing/degradation activity along with a combination with high throughput genomics, bioinformatics, and various ChIP-seq based experiments, we are able to predict long-range transcription enhancer function of the lncRNA-CSR locus. In this application, we continue to focus our investigation on the functionality of lncRNA-CSR and three other novel lncRNA expressing loci, that we propose to have a role in orchestrating DNA rearrangment events in germinal center resident B cells. B lymphocytes have the unique ability to undergo programmed somatic mutagenesis of their genomes (at immunoglobulin gene loci) to generate the diversity of antibodies required by our immune system to combat the plethora of antigens we might encounter, a process known as antibody diversification. However, as collateral damage emerging from this very unusual and useful ability to undertake beneficial somatic mutagenesis events is the ability of B cells accidently to mutate their genome at a very low frequency at various inappropriate locations. These accidental mutations are the cause of various B cell malignancies, particularly those that evolve from germinal center derived B cells. Interestingly, cancer-causing translocations in B cells occur at regions of divergent transcription—that is, promoters and enhancers—which exist inside topological domains of superenhancer clusters. We postulate that lncRNA-CSR is responsible for tethering long distant regulatory elements (i.e, promoters and enhancers) in the IgH locus superenhancer cluster to facilitate genome organization, transcription control of regulated genes, and, ultimately, to promote antibody diversification mechanisms without inducing cancer causing DNA alterations.

项目总结/摘要 越来越明显的是，大多数哺乳动物基因组都有可能 表达非编码RNA（ncRNA）。然而，监管的职能和机制 这些非编码RNA才刚刚开始被探索。生物学家遇到的一个挑战是 检测这些ncRNA，这往往是转录严格控制和快速 退化了我们最近发现了一个长的非编码（lnc）RNA表达位点，称为 lncRNA-CSR，调节B的免疫球蛋白重链（IgH）基因座中的DNA表达 细胞使用缺乏lncRNA加工/降解活性沿着有 结合高通量基因组学、生物信息学和各种基于ChIP-seq的 实验中，我们能够预测lncRNA-CSR的远程转录增强子功能， 基因座在本申请中，我们继续将研究重点放在lncRNA-CSR的功能上， 以及其他三个新的lncRNA表达位点，我们认为它们在协调DNA 生殖中心驻留B细胞中的再感染事件。B淋巴细胞具有独特的能力， 进行其基因组的程序性体细胞诱变（在免疫球蛋白基因座处）， 产生我们的免疫系统所需的抗体的多样性，以对抗过多的 我们可能遇到的抗原，这一过程被称为抗体多样化。但是，作为抵押品， 这种非常不寻常的和有用的能力，进行有益的身体损害出现 诱变事件是B细胞以非常低的频率意外地使其基因组突变的能力 在各种不合适的地方这些偶然的突变是各种B细胞 恶性肿瘤，特别是从生发中心衍生的B细胞进化而来的那些。有趣的是， 在B细胞中，致癌易位发生在趋异转录区域，即启动子 和增强子-其存在于超增强子簇的拓扑结构域内部。我们推测 lncRNA-CSR负责栓系远距离调节元件（即启动子和 增强子），以促进基因组的组织，转录 控制受调控的基因，并最终促进抗体多样化机制， 诱发癌症导致DNA改变