Agbaedeng, T. | Search bioRxiv

bioRxiv2024

Ox-LDL induces a non-inflammatory response enriched for coronary artery disease risk in human endothelial cells

Oxidised low-density lipoprotein cholesterol (ox-LDL) is critical in the initiation and progression of atherosclerosis. While excessive atherogenic lipids in the arterial intima can trigger endothelial dysfunction in advanced lesions, the response of endothelial cells to ox-LDL in the early stages of atherogenesis remains unclear. Here, we conducted a comprehensive, genome-wide multi-omics characterisation of the cellular response to ox-LDL in primary human aortic endothelial cells (HAECs). Our results reveal that the exposure of HAECs to ox-LDL leads to pathogenic changes in metabolism, transcriptome and epigenome, but in the absence of a typical inflammatory endothelial phenotype. An integrative analysis implicates the role of AP-1, NFE-2 and CEBP transcription factors in regulating ox-LDL-induced transcription. We further demonstrate that ox-LDL activates endothelial cell migration through the epigenomic rewiring of transcription factor binding. Notably, these ox-LDL-induced dynamic binding sites are enriched for the genetic risk of coronary artery disease, enabling the discovery of the gene-environment interaction of rs62172376 and ox-LDL at the CALCRL/TFPI locus. Collectively, our findings provide an unbiased understanding of the transcriptional regulation in endothelial cells in response to ox-LDL, together with its interaction with the genetic element of coronary artery disease.

genomics↗

bioRxiv2023

Partitioning heritability using single-cell multi-omics identifies a novel macrophage subpopulation conveying genetic risks of coronary artery disease.

BackgroundCoronary artery disease (CAD), the leading cause of death worldwide, is influenced by both environmental and genetic factors. While over 250 genetic risk loci have been identified through genome-wide association studies, the specific causal variants and their regulatory mechanisms are still largely unknown, particularly in disease-relevant cell types like macrophages. MethodsWe utilized single-cell RNA-seq (scRNA-seq) and single-cell multi-omics approaches in primary human monocyte-derived macrophages to explore the transcriptional regulatory network involved in a critical pathogenic event of coronary atherosclerosis--the formation of lipid-laden foam cells. Meta-analysis of scRNA-seq datasets from 26 human plaque samples was undertaken to provide a comprehensive atlas of lesional macrophages and to correlate subpopulations in vivo and ex vivo. The genetic risk levels of CAD were assessed by partitioning disease heritability across different macrophage subpopulations. ResultsWe identified a novel macrophage subpopulation, termed lipid-handling macrophages, both ex vivo and in vivo, and identified associated marker genes, transcription regulators, and functional pathways. 18,782 cis-regulatory elements were identified by jointly profiling the gene expression and chromatin accessibility of >5000 macrophages. Integration with CAD GWAS data prioritized 121 CAD-related genetic variants and 56 candidate causal genes. We showed that CAD heritability was not uniformly distributed and was particularly enriched in the gene programs of lipid-handling macrophages. We investigated the cis-regulatory effect of a risk variant rs10488763 on FDX1, implicating the recruitment of AP-1 and C/EBP-beta in the causal mechanisms at this locus. ConclusionsOur results provide genetic evidence of the divergent roles of macrophage subsets in atherogenesis and highlight lipid-handling macrophages as a key sub-population through which genetic variants actively influence disease. These findings provide an unbiased framework for functional fine-mapping of GWAS results using single-cell multi-omics and offer new insights into the genotype-environment interactions underlying atherosclerotic disease.

genetics↗