Mapping proximal and distal splicing-regulatory elements

绘制近端和远端剪接调控元件

• 批准号: 10669332
• 负责人: Chaolin Zhang
• 金额: $ 56.88万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-26 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669332
• 关键词: Affect; Affinity; Alternative Splicing; Binding; Biological Assay; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Color; Communities; Complex; Directed Molecular Evolution; Disease; Distal; Elements; Eligibility Determination; Engineering; Enhancers; Epigenetic Process; Exons; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Transcription; Genetic Variation; Genome; Genomics; Genotype; Goals; Guide RNA; Health; Human; Human Genetics; Human Genome; Intervention; Introns; Lentivirus; Libraries; Link; Malignant Neoplasms; Mammals; Maps; Methods; Molecular; Mus; Phenotype; Population; Post-Transcriptional Regulation; Protein Isoforms; Proteins; Quantitative Trait Loci; RNA; RNA Binding; RNA Splicing; RNA library; RNA-Binding Proteins; RNA-Protein Interaction; Regulation; Regulatory Element; Reporter; Research; Resolution; Resources; Source; System; Technology; Testing; Therapeutic; Transcript; Translating; Untranslated RNA; Variant; base; causal variant; clinical sequencing; clinically actionable; deep sequencing; density; driving force; functional genomics; genetic variant; genome wide association study; genomic data; high throughput screening; human disease; improved; mRNA Precursor; mutant; nervous system disorder; risk variant; single-cell RNA sequencing; technology development; tool; trait; transcriptome

Mapping proximal and distal splicing-regulatory elements PROJECT SUMMARY Alternative splicing (AS) of precursor mRNA is a molecular mechanism that allows single genes to generate multiple transcript and protein isoforms, providing a major driving force of molecular diversity in mammals including humans. AS is tightly regulated temporally and spatially to determine the types and level of protein products expressed in specific cellular contexts. Such regulation is dictated by numerous splicing-regulatory elements (SREs) in the alternative exon or flanking introns that are recognized by RNA-binding splicing factors. Aberrant splicing caused by disruption of SREs is implicated in an expanding list of genetic diseases ranging from neurological disorders to cancer, as well as phenotypic variation in human populations. This is reflected in recent findings that splicing quantitative trait loci (sQTLs) are as prevalent as gene expression QTLs, and they are similarly enriched in genetic variation associated with human diseases identified by GWAS. Despite the remarkable progress of the field, identification of causal splicing-disrupting variants has been severely impeded by the lack of comprehensive SRE annotations in the human genome, as compared to similar maps of transcriptional or epigenetic regulatory elements. To fill in this tremendous gap, this study proposes an unbiased, high-throughput screening approach to map functional SREs, including those in distal regions that are largely overlooked by current studies. If successful, this platform technology will facilitate the genomic research community to study gene expression regulation, understand genotype-phenotype relationships, and interpret the impact of genetic variation in human diseases.

定位近端和远端剪接调控元件 项目摘要 前体mRNA的选择性剪接（AS）是一种允许单个基因产生 多种转录物和蛋白质异构体，为哺乳动物的分子多样性提供了主要驱动力 包括人类AS在时间和空间上受到严格调控，以决定蛋白质的类型和水平 在特定细胞环境中表达的产物。这种调节是由许多拼接调节决定的。 选择性外显子或侧翼内含子中的SRE，其被RNA结合剪接因子识别。 由SRE破坏引起的异常剪接与越来越多的遗传疾病有关， 从神经系统疾病到癌症，以及人类群体中的表型变异。这反映在 最近的研究发现，剪接数量性状基因座（sQTL）和基因表达QTL一样普遍， 同样富含与GWAS鉴定的人类疾病相关的遗传变异。尽管 尽管该领域取得了显著进展，但因果性剪接破坏变体的鉴定受到严重阻碍 由于人类基因组中缺乏全面的SRE注释，与人类基因组的类似图谱相比， 转录或表观遗传调控元件。为了填补这一巨大的空白，这项研究提出了一个公正的， 高通量筛选方法来定位功能性SRE，包括那些在远端区域， 被目前的研究所忽视。如果成功，该平台技术将促进基因组研究 社区研究基因表达调控，了解基因型-表型关系，并解释 基因变异对人类疾病的影响。