New Methods to Uncover Global Transcriptional Programs for Disease Risk Variants

揭示疾病风险变异全球转录程序的新方法

基本信息

批准号：
8644271
负责人：
YOUSIN SUH
金额：
$ 61.18万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-05 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8644271
关键词：
9p21 Address Aging Alleles Alternative Splicing Antisense Oligonucleotides Antisense RNA Architecture Binding Biological CDKN2A gene CDKN2B gene Cells Chronic Disease Clinical Code Conflict (Psychology)Coronary Arteriosclerosis Coupled DNA Sequence Data Development Disease Disease Progression Disease susceptibility Endothelial Cells Engineering Enhancers Epigenetic Process Etiology Event Functional RNA Gene Expression Genes Genetic Genetic Transcription Genome Genomics Genotoxic Stress Genotype Goals Health Higher Order Chromatin Structure Human Human Biology Individual Inflammation Inflammatory Investigation Junk DNA Laboratories Licensing Link Location Malignant Neoplasms Maps Methodology Methods Modeling Molecular Mus Nature Non-Insulin-Dependent Diabetes Mellitus Nuclear Nucleic Acid Regulatory Sequences Oncogenes Outcome Pathway interactions Pattern Protein Isoforms Proteins Publishing RNA RNA Splicing Regulation Reporting Risk Role Sequence Analysis Signal Transduction Site Stress Structure Technology Testing Therapeutic Transcript Translating Variant age related base disease phenotype disorder prevention disorder risk epigenomics genome wide association study genome-wide human disease insight locked nucleic acid lymphoblast lymphoblastoid cell line macrophage novel novel therapeutics prevent programs promoter response risk variant senescence success trait transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): More than 1,000 published GWAS have collectively reported significant associations of ~4,000 SNPs for more than 200 traits/diseases. The challenge is to move SNP associations to biological insights and then to translate these insights, achieving better clinical outcomes. This ambitious goal requires an inclusive and effective strategy to solve the molecular basis by which these variants confer disease susceptibility. To date, the vast majority of the associations noted in GWAS for disease phenotypes have been with variants located within gene deserts, the 99% of the genome that does not encode known proteins and where our understanding of functional consequences and causality is at best rudimentary. Recent findings indicate that altering DNA sequence in evolutionarily conserved non-coding regions can be as deleterious as altering coding regions. Therefore, it is not surprising that disease-causing variants will reside in the gene desert regions. The greatest challenge in the "post-GWAS" era is to understand the regulatory principles of risk variants in gene desert regions and the mechanisms underlying the risk conferred by these loci. The goal of this proposal is to accelerate post-GWAS functional characterization, uncovering initial global principles for the functional characterization of disease risk loci by focusing on altered function in transcription based on the actions of enhancer RNAs. Employing the 9p21 region as a model, we will establish how disease-associated common sequence variants alter the functions of regulatory regions and address the molecular mechanisms by which these effects are exerted. These studies will integrate disease susceptibility-associated sequence variations into the emerging three-dimensional network of long-distance genomic region interactions, establish local and global alterations in gene transcription, and explore the key role of enhancer-RNAs harboring sequence variations at GWAS loci. The primary significance will be the discovery of a novel functional consequences and an "epigenomic" molecular mechanism underlying GWAS loci in disease, with the opportunity for exploiting these new mechanistic and therapeutic insights for preventative approaches to the chronic diseases associated with aging.

描述（由申请人提供）：超过 1,000 个已发表的 GWAS 共同报告了约 4,000 个 SNP 与 200 多种性状/疾病的显着关联。挑战在于将 SNP 关联转化为生物学见解，然后转化这些见解，实现更好的临床结果。这一雄心勃勃的目标需要一种包容性和有效的策略来解决这些变异赋予疾病易感性的分子基础。迄今为止，GWAS 中指出的疾病表型的绝大多数关联都与位于基因荒漠内的变异有关，即 99% 的基因组不编码已知蛋白质，而我们对功能后果和因果关系的理解充其量只是初级的。最近的研究结果表明，改变进化上保守的非编码区的 DNA 序列可能与改变编码区一样有害。因此，致病变异存在于基因沙漠区域也就不足为奇了。 “后GWAS”时代最大的挑战是了解基因沙漠地区风险变异的调控原理以及这些位点赋予风险的机制。该提案的目标是加速 GWAS 后功能表征，通过关注改变的功能来揭示疾病风险位点功能表征的初步全球原则基于增强子 RNA 的作用进行转录。使用 9p21 区域作为模型，我们将确定与疾病相关的常见序列变异如何改变调节区域的功能，并探讨发挥这些作用的分子机制。这些研究将把与疾病易感性相关的序列变异整合到新兴的长距离基因组区域相互作用的三维网络中，建立基因转录的局部和全局改变，并探索在 GWAS 位点上隐藏序列变异的增强子 RNA 的关键作用。主要意义在于发现疾病中 GWAS 位点的新功能后果和“表观基因组”分子机制，并有机会利用这些新的机制和治疗见解来预防与衰老相关的慢性疾病。