Cis-regulatory architecture of coronary vascular wall loci

冠状血管壁位点的顺式调控结构

• 批准号: 10609005
• 负责人: Clint L Miller
• 金额: $ 40.53万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609005
• 关键词: Address; Affect; Architecture; Arterial Fatty Streak; Arteries; Atherosclerosis; Automobile Driving; Binding; Biological; Biological Assay; Blood Vessels; Blood flow; Candidate Disease Gene; Cell Line; Cells; Chromatin; Chromatin Structure; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Coronary; Coronary Arteriosclerosis; Coronary artery; Coupled; Data Set; Developing Countries; Disease; Disease susceptibility; EP300 gene; Early Diagnosis; Engineering; Environmental Risk Factor; Evaluation; Fibroblasts; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Variation; Genetic study; Genomic Segment; Genomics; Genotype; Genotype-Tissue Expression Project; Goals; Heart; Heterogeneity; Human; Individual; Intervention; Joints; Knowledge; Link; MADH3 gene; Macrophage; Maps; Measures; Mediating; Mendelian randomization; Messenger RNA; Meta-Analysis; Mission; Myocardial Infarction; Pathogenesis; Pathway interactions; Phenotype; Play; Population; Prevalence; Prevention strategy; Process; Proliferating; Public Health; Quantitative Trait Loci; RNA; RNA Splicing; Regulator Genes; Regulatory Element; Repression; Research; Resolution; Role; Sampling; Single Nucleotide Polymorphism; Smooth Muscle Myocytes; Therapeutic; Time; Tissues; Translating; Transposase; United States National Institutes of Health; Untranslated RNA; Variant; Work; biobank; causal variant; cell type; clinically relevant; cohort; disorder risk; epigenomics; genetic risk factor; genome wide association study; genomic locus; human disease; human tissue; in silico; insight; migration; mortality; mouse model; multiple omics; next generation; novel; programs; response to injury; risk variant; single cell analysis; single-cell RNA sequencing; transcription factor; transcription factor USF; transcriptome sequencing; treatment strategy

PROJECT SUMMARY Coronary artery disease (CAD) remains the leading cause of mortality worldwide and poses considerable public health burden. Both genetic and environmental risk factors contribute to CAD susceptibility, leading to increased disease prevalence in developing countries. Genome-wide association studies (GWAS) have now identified 161 independent genetic loci associated with CAD risk in large-scale meta-analyses in over 300,000 individuals. However, given that the majority of the associations reside in non-coding genomic regions, it has been challenging to translate these discoveries into biologically and clinically relevant insights. Interestingly, many of the candidate genes at CAD loci are organized into novel or unknown biological pathways, and point to dysregulation of vascular wall processes. Large efforts such as the Genotype Tissue Expression (GTEx) project and Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study have refined candidate gene regulatory mechanisms, however the specific cellular and phenotypic states driving these changes remains unclear. Smooth muscle cells (SMC) normally regulate vascular tone in the vessel wall but play critical roles in disease pathogenesis as their contractile gene program is hijacked during phenotypic switching to macrophage-like and fibroblast-like cells. Using epigenomic and expression quantitative trait loci (eQTL) mapping in 52 primary human coronary artery smooth muscle cells (HCASMC) we recently identified 11 candidate causal genes and mechanisms linking vascular wall processes to CAD risk (e.g. TCF21, SMAD3, CDKN2B, LMOD1). It is likely that non-coding regulatory variants function through changes in chromatin accessibility, which coincides with transcription factor (TF) binding in cis. By identifying these upstream TFs at vascular wall loci we can begin to assemble targetable pathways to modulate hidden disease risk in the vessel wall. In this proposal we plan to perform joint gene expression and chromatin accessibility QTL mapping in a unique cohort of 120 normal and diseased coronary artery tissues from explanted heart donors. We will validate and discover functional regulatory elements at GWAS loci using CRISPR/dCas9 perturbation with high-throughput phenotyping in SMC. Finally, we will investigate the cis-regulatory architecture in these samples at single-cell resolution and infer TF binding during phenotypic modulation. Together these studies will reveal the causal regulatory mechanisms responsible for CAD in the vascular wall and inform next generation treatment or prevention strategies to eradicate this debilitating disease.

项目总结

项目成果

Leukocytes carrying Clonal Hematopoiesis of Indeterminate Potential (CHIP) Mutations invade Human Atherosclerotic Plaques.

携带不确定电位克隆造血 (CHIP) 突变的白细胞侵入人类动脉粥样硬化斑块。

• DOI: 10.1101/2023.07.22.23292754
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: vonScheidt,Moritz;Bauer,Sabine;Ma,Angela;Hao,Ke;Kessler,Thorsten;Vilne,Baiba;Wang,Ying;Hodonsky,ChaniJ;Ghosh,SaikatKB;Mokry,Michal;Gao,Hua;Kawai,Kenji;Sakamoto,Atsushi;Kaiser,Juliane;Bongiovanni,Dario;Fleig,Julia;Oldenb
• 通讯作者: Oldenb

Prediction of causal genes at GWAS loci with pleiotropic gene regulatory effects using sets of correlated instrumental variables.

使用一组相关的工具变量预测具有多效性基因调控效应的 GWAS 位点的因果基因。

• 发表时间: 2024
• 期刊: ArXiv
• 作者: Khan,Mariyam;Ludl,Adriaan;Bankier,Sean;Björkegren,JohanLm;Michoel,Tom
• 通讯作者: Michoel,Tom

Transcriptomic-based clustering of human atherosclerotic plaques identifies subgroups with different underlying biology and clinical presentation.

• DOI: 10.1038/s44161-022-00171-0
• 发表时间: 2022-12
• 期刊: Nature cardiovascular research
• 作者: M. Mokry;A. Boltjes;L. Slenders;Gemma Bel-Bordes;Kai Cui;E. Brouwer;J. Mekke;M. Depuydt;N. Timmerman;F. Waissi;M. Verwer;A. Turner;Mohammad Daud Khan;C. Hodonsky;E. Diez Benavente;R. Hartman;N. V. D. van den Dungen;N. Lansu;Emilia Nagyova;K. Prange;J. Kovacic;J. Björkegren;Eleftherios Pavlos;E. Andreakos;H. Schunkert;G. Owens;C. Monaco;A. Finn;R. Virmani;N. Leeper;M. D. de Winther;J. Kuiper;G. D. de Borst;E. Stroes;M. Civelek;D. D. de Kleijn-D.;H. D. den Ruijter;F. Asselbergs;S. W. van der Laan;Clint L. Miller;G. Pasterkamp