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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.

项目摘要/摘要