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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要越来越明显的是，大多数哺乳动物基因组都有潜力然而，表达非编码 RNA (ncRNA) 的功能和调节机制。这些 ncRNA 的探索才刚刚开始。检测这些 ncRNA，这些 ncRNA 通常受到转录严格控制且快速我们最近发现了一个长非编码 (lnc) RNA 表达位点，称为 lncRNA-CSR，调节 B 的免疫球蛋白重链 (IgH) 位点中的 DNA 重排使用缺乏 lncRNA 加工/降解活性以及与高通量基因组学、生物信息学和各种基于 ChIP-seq 的结合实验中，我们能够预测lncRNA-CSR的长程转录增强子功能在此应用中，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，我们建议它们在编排 DNA 中发挥作用生发中心驻留 B 淋巴细胞中的重排事件具有独特的能力。对其基因组（免疫球蛋白基因位点）进行程序性体细胞诱变产生我们的免疫系统所需的多样性抗体来对抗过多的病毒我们可能会遇到抗原，这一过程称为抗体多样化。从这种非常不寻常的情况中出现并损害了进行有益的躯体的有用能力诱变事件是 B 细胞意外地以非常低的频率突变其基因组的能力这些意外的突变是各种B细胞的原因。恶性肿瘤，特别是那些由生发中心衍生的 B 细胞进化而来的恶性肿瘤。 B 细胞中的致癌易位发生在转录差异区域，即启动子区域和增强子——存在于超级增强子簇的拓扑域内。 lncRNA-CSR 负责束缚长距离调控元件（即启动子和 IgH 基因座超级增强子簇中的增强子）促进基因组组织、转录控制受调节的基因，并最终促进抗体多样化机制，而无需诱发癌症，导致 DNA 改变。