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多个已发表的GWAS共同报告了200多种特征/疾病的约4,000个SNP的显着关联。面临的挑战是将SNP关联转移到生物学见解，然后转化这些见解，从而获得更好的临床结果。这个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体赋予疾病易感性的分子基础。迄今为止，GWAS疾病表型中指出的绝大多数关联是位于基因沙漠中的变体，这是没有编码已知蛋白质的99％的基因组，以及我们对功能后果和因果关系的理解最佳的基因组。最近的发现表明，在进化保守的非编码区域中的DNA序列改变可能与改变编码区一样有害。因此，毫不奇怪的是，引起疾病的变体将位于基因沙漠地区。 “后GWAS”时代的最大挑战是了解基因沙漠地区风险变异的监管原理以及这些基因座赋予风险的基础机制。该提案的目的是加速GWAS后功能表征，通过专注于改变功能来揭示疾病风险基因座功能表征的最初全球原理在基于增强子RNA的作用的转录中。我们将采用9P21区域作为模型，我们将确定与疾病相关的共同序列变体如何改变调节区域的功能并解决这些作用的分子机制。这些研究将将疾病易感性相关的序列变化整合到长距离基因组区域相互作用的新兴三维网络中，在基因转录中建立了局部和全局变化，并探索了GWASI位于GWASI的增强子RNAS的关键作用。主要意义将是发现新型功能后果和疾病中GWAS基因座基础的“表观基因组”分子机制，并有机会利用这些新的机械和治疗性见解，以解决与年龄相关的慢性疾病的预防方法。