Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci

Miller, Clint L.; Pjanic, Milos; Wang, Ting; Nguyen, Trieu; Cohain, Ariella; Lee, Jonathan D.; Perisic, Ljubica; Hedin, Ulf; Kundu, Ramendra K.; Majmudar, Deshna; Kim, Juyong Brian; Wang, Oliver; Betsholtz, Christer; Ruusalepp, Arno; Franzén, Oscar; Assimes, Themistocles L.; Montgomery, Stephen B.; Schadt, Eric E.; Björkegren, Johan; Quertermous, Thomas

doi:10.1038/ncomms12092

Cited by 124 publications

(150 citation statements)

References 70 publications

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“…We generated high-resolution enhancer–promoter maps from primary human coronary artery smooth muscle cells (HCASMCs), which can be used to inform on variants linked to cardiovascular diseases 41 . First, to validate cell type specificity, we examined the gene promoter for TCF21 , a transcription factor required for the differentiation of HCASMCs 42 , and observed enrichment of HCASMC EIS relative to naive T cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Enhancer connectome in primary human cells identifies target genes of disease-associated DNA elements

et al. 2017

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The challenge of linking intergenic mutations to target genes has limited molecular understanding of human diseases. Here we show that H3K27ac HiChIP generates high-resolution contact maps of active enhancers and target genes in rare primary human T cell subtypes and coronary artery smooth muscle cells. Differentiation of naive T cells into T helper 17 cells or regulatory T cells creates subtype-specific enhancer–promoter interactions, specifically at regions of shared DNA accessibility. These data provide a principled means of assigning molecular functions to autoimmune and cardiovascular disease risk variants, linking hundreds of noncoding variants to putative gene targets. Target genes identified with HiChIP are further supported by CRISPR interference and activation at linked enhancers, by the presence of expression quantitative trait loci, and by allele-specific enhancer loops in patient-derived primary cells. The majority of disease-associated enhancers contact genes beyond the nearest gene in the linear genome, leading to a fourfold increase in the number of potential target genes for autoimmune and cardiovascular diseases.

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Section: Resultsmentioning

confidence: 99%

“…First, HCASMC phasing data 41 were used to mask the hg19 genome and make indexes. HiC-Pro settings were similar to those described above, with the exception that reads were aligned to the masked genome and then assigned to a specific allele on the basis of phasing data.…”

Section: Methodsmentioning

confidence: 99%

Enhancer connectome in primary human cells identifies target genes of disease-associated DNA elements

et al. 2017

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“…[33] We identified SNP rs10265174 to be one of the top eQTLs for AHR (p<9e-5) (Fig 3A and 3B). Also, rs10265174 was consistently found to regulate gene expression in multiple GTEx tissues, including coronary artery, aorta and tibial artery (S4 Table).…”

Section: Resultsmentioning

confidence: 99%

TCF21 and the environmental sensor aryl-hydrocarbon receptor cooperate to activate a pro-inflammatory gene expression program in coronary artery smooth muscle cells

et al. 2017

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Both environmental factors and genetic loci have been associated with coronary artery disease (CAD), however gene-gene and gene-environment interactions that might identify molecular mechanisms of risk are not easily studied by human genetic approaches. We have previously identified the transcription factor TCF21 as the causal CAD gene at 6q23.2 and characterized its downstream transcriptional network that is enriched for CAD GWAS genes. Here we investigate the hypothesis that TCF21 interacts with a downstream target gene, the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates the cellular response to environmental contaminants, including dioxin and polycyclic aromatic hydrocarbons (e.g., tobacco smoke). Perturbation of TCF21 expression in human coronary artery smooth muscle cells (HCASMC) revealed that TCF21 promotes expression of AHR, its heterodimerization partner ARNT, and cooperates with these factors to upregulate a number of inflammatory downstream disease related genes including IL1A, MMP1, and CYP1A1. TCF21 was shown to bind in AHR, ARNT and downstream target gene loci, and co-localization was noted for AHR-ARNT and TCF21 binding sites genome-wide in regions of HCASMC open chromatin. These regions of co-localization were found to be enriched for GWAS signals associated with cardio-metabolic as well as chronic inflammatory disease phenotypes. Finally, we show that similar to TCF21, AHR gene expression is increased in atherosclerotic lesions in mice in vivo using laser capture microdissection, and AHR protein is localized in human carotid atherosclerotic lesions where it is associated with protein kinases with a critical role in innate immune response. These data suggest that TCF21 can cooperate with AHR to activate an inflammatory gene expression program that is exacerbated by environmental stimuli, and may contribute to the overall risk for CAD.

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“…110,111 The connectivity structure of networks in disease helps us understand how biological processes are defined at the molecular level, how they are disrupted in disease, and how we can assess disease risk and potentially intervene. 110,111 Causal network approaches have been applied to several disease areas outside of allergy, resulting in new mechanistic understandings for metabolic disease, 112 cardiovascular disease, 113 and Alzheimer disease. 114 The implementation of such systems biology approaches to better understand the role of the microbiome in patients with asthma, AD, and food allergy represents a challenge to be addressed in the future.…”

Section: Challenges and Research Opportunitiesmentioning

confidence: 99%

The microbiome in allergic disease: Current understanding and future opportunities—2017 PRACTALL document of the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology

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et al. 2017

Journal of Allergy and Clinical Immunology

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PRACTALL is a joint initiative of the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology to provide shared evidence-based recommendations on cutting-edge topics in the field of allergy and immunology. PRACTALL 2017 is focused on what has been established regarding the role of the microbiome in patients with asthma, atopic dermatitis, and food allergy. This is complemented by outlining important knowledge gaps regarding its role in allergic disease and delineating strategies necessary to fill these gaps. In addition, a review of progress in approaches used to manipulate the microbiome will be addressed, identifying what has and has not worked to serve as a baseline for future directions to intervene in allergic disease development, progression, or both.

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Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci

Cited by 124 publications

References 70 publications

Enhancer connectome in primary human cells identifies target genes of disease-associated DNA elements

Enhancer connectome in primary human cells identifies target genes of disease-associated DNA elements

TCF21 and the environmental sensor aryl-hydrocarbon receptor cooperate to activate a pro-inflammatory gene expression program in coronary artery smooth muscle cells

The microbiome in allergic disease: Current understanding and future opportunities—2017 PRACTALL document of the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology

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