权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Long noncoding RNA expressing genomic elements 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：
10531294
负责人：
Uttiya Basu
金额：
$ 58.96万
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 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10531294
关键词：
3-Dimensional Antibodies Architecture B-Cell Development B-Lymphocytes Binding Sites Biochemical Biological Assay Biological Models Biology CRISPR/Cas technology CSPG6 gene Cell Line Chromatin Conformation Capture and Sequencing Chromosomal translocation Chromosomes Complex Control Locus DNA DNA Maintenance DNA Sequence Alteration Data Detection Development Disease Elements Enhancers Event Experimental Genetics Genes Genetic Genetic Enhancer Element Genetic Polymorphism Genetic Recombination Genetic Transcription Genome Genomics Grant High-Throughput Nucleotide Sequencing Homeostasis Human Hybrids IGH@ gene cluster IgA Deficiency Immune system Immunity Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Immunoglobulins Immunologics Impairment Libraries Lymphoma Lymphomagenesis Mediating Modeling Molecular Molecular Mechanisms of Action Mutation Nomenclature Patients Peyer&apos s Patches Physiological Physiology Post-Transcriptional RNA Processing Proteins Publishing RNA RNA analysis RNA-Protein Interaction Regulation Regulatory Element Research Design Role Scanning Site Structure Syndrome System Transcript Untranslated RNA chromatin immunoprecipitation cohesin dysbiosis exosome experimental study genome integrity genome-wide genomic locus humoral immunity deficiency mammalian genome microbiome mouse genome mouse model novel prevent recruit repaired trafficking transcriptomics

项目摘要

PROJECT SUMMARY Background. It is now 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. Using mouse models that allow easy detection of lncRNA, we have recently identified a set of long noncoding RNAs (lncRNA) that are expressed surrounding the immunoglobulin loci genes. These lncRNAs are placed inside topologically associating domains (TADs) that are formed during B cell development. Experiments using mouse models that lack these lncRNAs (published and preliminary data) demonstrate roles in class switch recombination and somatic hypermutation mechanisms. Objectives/Hypothesis. Here we investigate the direct role of lncRNAs in regulating genome local architecture and DNA topology via cis and trans mechanisms. In aim 1: we evaluate the physiological role of lncRNA-expressing loci in regulating IgH recombination via organizing TADIgH; in aim 2, we understand the molecular mechanisms through which lncRNAs are used to control genome architecture; and in aim 3, we focus on understanding the function of lncRNA SµGLT in control of CSR. Study Design: Using mouse models and cell lines that are deficient in specific lncRNAs we aim to investigate their immunologically relevant functions. For evaluating the molecular mechanism of action of the lncRNAs we use biochemical assays to purify lncRNA interacting proteins and perform chromosomal architecture assays such as HiC and 4C-seq. Finally, we perform high-throughput sequencing experiments to evaluate the lncRNA's effect(s) on SHM in the Ig loci genes and elsewhere. Disease Relevance: The proposed studies will lead to a better understanding of the mechanisms in B cell development and function. The lncRNAs being investigated in this application carry polymorphisms in patients with IgA deficiency syndrome and thus our study is relevant for human physiology. Finally, antibody diversification mechanisms are essential for immune system homeostasis but when these mechanisms fail there are increased genomic alterations that are associated with lymphomas. Thus, this study is related with both immunity and lymphomagenesis.

项目总结