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Quertermous, T.

Publications and source records attributed to Quertermous, T..

24 records · Page 2Linked to original sources
bioRxiv2020

Quantitative trait loci mapped for TCF21 binding, chromatin accessibility and chromosomal looping in coronary artery smooth muscle cells reveal molecular mechanisms of coronary disease loci

BackgroundTo investigate the epigenetic and transcriptional mechanisms of coronary artery disease (CAD) risk, as well as the functional regulation of chromatin structure and function, we have created a catalog of genetic variants associated with three stages of transcriptional cis-regulation in primary human coronary artery vascular smooth muscle cells (HCASMC). ResultsTo this end, we have used a pooling approach with HCASMC lines to map regulatory variation that mediates binding of the CAD associated transcription factor TCF21 with ChIPseq studies (bQTLs), variation that regulates chromatin accessibility with ATACseq studies (caQTLs), and chromosomal looping with HiC methods (clQTLs). We show significant overlap of the QTLs, and their relationship to smooth muscle specific genes and the binding of smooth muscle transcription factors. Further, we use multiple analyses to show that these QTLs are highly associated with CAD GWAS loci and correlated to lead SNPs in these loci where they show allelic effects. We have verified with genome editing that identified functional variants can regulate both chromatin accessibility and chromosomal looping, providing new insights into functional mechanisms regulating chromatin state and chromosomal structure. Finally, we directly link the disease associated TGF{beta}1-SMAD3 pathway to the CAD associated FN1 gene through a response QTL that modulates both chromatin accessibility and chromosomal looping. ConclusionsTogether, these studies represent the most thorough mapping of multiple QTL types in a highly disease relevant primary cultured cell type, and provide novel insights into their functional overlap and mechanisms that underlie these genomic features and their relationship to disease risk.

genomics↗
bioRxiv2019

Long non-coding RNA gene regulation and trait associations across human tissues

Long non-coding RNA (lncRNA) genes are known to have diverse impacts on gene regulation. However, it is still a major challenge to distinguish functional lncRNAs from those that are byproducts of surrounding transcriptional activity. To systematically identify hallmarks of biological function, we used the GTEx v8 data to profile the expression, regulation, network relationships and trait associations of lncRNA genes across 49 tissues encompassing 87 distinct traits. In addition to revealing widespread differences in regulatory patterns between lncRNA and protein-coding genes, we identified novel disease-associated lncRNAs, such as C6orf3 for psoriasis and LINC01475/RP11-129J12.1 for ulcerative colitis. This work provides a comprehensive resource to interrogate lncRNA genes of interest and annotate cell type and human trait relevance.\n\nOne Sentence SummarylncRNA genes have distinctive regulatory patterns and unique trait associations compared to protein-coding genes.

genetics↗
bioRxiv2018

Genetic regulatory mechanisms of smooth muscle cells map to coronary artery disease risk loci

Coronary artery disease (CAD) is the leading cause of death globally. Genome-wide association studies (GWAS) have identified more than 95 independent loci that influence CAD risk, most of which reside in non-coding regions of the genome. To interpret these loci, we generated transcriptome and whole-genome datasets using human coronary artery smooth muscle cells (HCASMC) from 52 unrelated donors, as well as epigenomic datasets using ATAC-seq on a subset of 8 donors. Through systematic comparison with publicly available datasets from GTEx and ENCODE projects, we identified transcriptomic, epigenetic, and genetic regulatory mechanisms specific to HCASMC. We assessed the relevance of HCASMC to CAD risk using transcriptomic and epigenomic level analyses. By jointly modeling eQTL and GWAS datasets, we identified five genes (SIPA1, TCF21, SMAD3, FES, and PDGFRA) that modulate CAD risk through HCASMC, all of which have relevant functional roles in vascular remodeling. Comparison with GTEx data suggests that SIPA1 and PDGFRA influence CAD risk predominantly through HCASMC, while other annotated genes may have multiple cell and tissue targets. Together, these results provide new tissue-specific and mechanistic insights into the regulation of a critical vascular cell type associated with CAD in human populations.

genomics↗
bioRxiv2017

Vulnerabilities of transcriptome-wide association studies

Transcriptome-wide association studies (TWAS) integrate GWAS and gene expression datasets to find gene-trait associations. In this Perspective, we explore properties of TWAS as a potential approach to prioritize causal genes, using simulations and case studies of literature-curated candidate causal genes for schizophrenia, LDL cholesterol and Crohns disease. We explore risk loci where TWAS accurately prioritizes the likely causal gene, as well as loci where TWAS prioritizes multiple genes, some of which are unlikely to be causal, because they share the same variants as eQTLs. We illustrate that TWAS is especially prone to spurious prioritization when using expression data from tissues or cell types that are less related to the trait, due to substantial variation in both expression levels and eQTL strengths across cell types. Nonetheless, TWAS prioritizes candidate causal genes at GWAS loci more accurately than simple baselines based on proximity to lead GWAS variant and expression in trait-related tissue. We discuss current strategies and future opportunities for improving the performance of TWAS for causal gene prioritization. Our results showcase the strengths and limitations of using expression variation across individuals to determine causal genes at GWAS loci and provide guidelines and best practices when using TWAS to prioritize candidate causal genes.

genetics↗
bioRxiv2017

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

The challenge of linking intergenic mutations to target genes has limited molecular understanding of diverse human diseases. Here, we show 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 to either T helper 17 cells or regulatory T cells create 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 four-fold increase of potential target genes for autoimmune and cardiovascular diseases.

genomics↗