Functional Characterization of the Genetic and Environmental Determinants of Complex Traits

复杂性状的遗传和环境决定因素的功能表征

• 批准号: 10172918
• 负责人: Francesca Luca
• 金额: $ 29.72万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10172918
• 关键词: ATAC-seq; Alleles; Base Pairing; Binding; Biological Assay; Cell model; Chromatin; Complex; Computing Methodologies; Data; Disease; Environment; Epigenetic Process; Etiology; Evaluation; Gene Expression; Gene Expression Regulation; Genetic; Genetic Risk; Genetic Variation; Genomics; Genotype-Tissue Expression Project; Glucocorticoid Receptor; Glucocorticoids; Hormones; Human; In Vitro; Individual; Ions; Link; Measures; Metals; Methods; Modeling; Molecular; Nucleotides; Pathologic; Pathway interactions; Pharmaceutical Preparations; Phenotype; Proxy; Regulatory Element; Reporter; Research Personnel; Resolution; Resources; Risk; Role; Signal Transduction; Tissues; Untranslated RNA; Variant; Vitamins; Work; biological adaptation to stress; causal variant; convolutional neural network; functional genomics; gene discovery; gene environment interaction; genetic analysis; genetic association; genetic variant; genome wide association study; genomic data; improved; interest; prediction algorithm; predictive modeling; predictive signature; quasar; response; trait; transcription factor; transcriptome sequencing

Understanding the molecular and organismal function of genetic variants in non-coding regions is crucial to dissect the genetic and evolutionary basis of variation in complex traits. Combining complementary functional genomics datasets has proven a successful strategy to pinpoint the most likely causal variant and molecular mechanism supporting a genetic association. Current existing annotations only capture regulatory conditions at the baseline level. However, as we and others have shown, the effect of a genetic variant on a molecular pathway, and ultimately on the individual's phenotype, may be modulated by the cellular environmental context (gene-environment interactions, GxE). We define these genetic variants as GxE quantitative trait nucleotides (GxE-QTNs) and consider the cellular environment as a simplified but better controlled proxy of the organismal environment. Binding of TFs to specific genomic targets is defined by sequence motifs and chromatin epige- netic marks, and can be altered by the presence of GxE-QTNs. To discover genes modulated by GxE-QTNs, we have recently established a high-throughput approach to perturb the cellular environment by a panel of 50 in vitro treatments, including vitamins, metal ions, common drugs and hormones. Here we propose to use this approach to dissect these GxE-QTNs and the underlying molecular mechanism by: i) performing functional ge- nomics assays capturing chromatin accessibility; ii) analyzing the effects of naturally occurring genetic variation in regulatory elements; and iii) combining RNA-seq, ATAC-seq, MPRA and GWAS data to co-localize association signals and pinpoint complex traits causal variants.

了解非编码区遗传变异的分子和生物学功能对于 剖析复杂性状变异的遗传和进化基础。组合互补泛函 基因组学数据集已被证明是一种成功的策略，可以确定最可能的致病变异和分子 支持遗传关联的机制。当前现有注释仅捕获监管条件 在基线水平。然而，正如我们和其他人所表明的，遗传变异对分子生物学的影响， 通路，并最终对个体的表型，可能是由细胞环境背景调制 基因与环境的相互作用（Gene-environment interactions，GxE）我们将这些遗传变异定义为GxE数量性状核苷酸 （GxE-QTN），并考虑细胞环境作为一个简化的艾德，但更好地控制代理的有机体 环境TF与特定基因组靶标的结合由序列基序和染色质表位定义。 遗传标记，并且可以通过GxE-QTN的存在而改变。为了发现受GxE-QTN调节的基因， 我们最近建立了一种高通量的方法，通过一组50个 体外治疗，包括维生素、金属离子、常用药物和激素。在这里，我们建议使用这个 方法来剖析这些GxE-QTN和潜在的分子机制，通过：i）进行功能性基因工程， 捕获染色质可及性的组学测定; ii）分析天然存在的遗传变异的影响 iii）组合RNA-seq、ATAC-seq、MPRA和GWAS数据以共定位关联 信号和精确定位复杂性状的因果变异。

项目成果

Environmental influences on RNA processing: Biochemical, molecular and genetic regulators of cellular response.

• DOI: 10.1002/wrna.1503
• 发表时间: 2019-01
• 期刊: Wiley interdisciplinary reviews. RNA
• 作者: Pai AA;Luca F
• 通讯作者: Luca F

Genetic control of the dynamic transcriptional response to immune stimuli and glucocorticoids at single-cell resolution.

单细胞分辨率下对免疫刺激和糖皮质激素的动态转录反应的遗传控制。

• DOI: 10.1101/gr.276765.122
• 发表时间: 2023-06
• 期刊: GENOME RESEARCH
• 影响因子: 7
• 作者: Resztak, Justyna A.;Wei, Julong;Zilioli, Samuele;Sendler, Edward;Alazizi, Adnan;Mair-Meijers, Henriette E.;Wu, Peijun;Wen, Xiaoquan;Slatcher, Richard B.;Zhou, Xiang;Luca, Francesca;Pique-Regi, Roger
• 通讯作者: Pique-Regi, Roger

Interspecies variation in hominid gut microbiota controls host gene regulation.

人类肠道微生物群的种间变化控制宿主基因调节。

• DOI: 10.1016/j.celrep.2021.110057
• 发表时间: 2021-11-23
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Muehlbauer AL;Richards AL;Alazizi A;Burns MB;Gomez A;Clayton JB;Petrzelkova K;Cascardo C;Resztak J;Wen X;Pique-Regi R;Luca F;Blekhman R
• 通讯作者: Blekhman R

Which Genetics Variants in DNase-Seq Footprints Are More Likely to Alter Binding?

• DOI: 10.1371/journal.pgen.1005875
• 发表时间: 2016-02
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Moyerbrailean GA;Kalita CA;Harvey CT;Wen X;Luca F;Pique-Regi R
• 通讯作者: Pique-Regi R

Environmental Enrichment Induces Epigenomic and Genome Organization Changes Relevant for Cognition.

• DOI: 10.3389/fnmol.2021.664912
• 发表时间: 2021
• 期刊: Frontiers in molecular neuroscience
• 影响因子: 4.8
• 作者: Espeso-Gil S;Holik AZ;Bonnin S;Jhanwar S;Chandrasekaran S;Pique-Regi R;Albaigès-Ràfols J;Maher M;Permanyer J;Irimia M;Friedländer MR;Pons-Espinal M;Akbarian S;Dierssen M;Maass PG;Hor CN;Ossowski S
• 通讯作者: Ossowski S