Integrative Multi-Omics Analysis of IFNγ-induced Macrophages and Atherosclerotic Plaques Reveals Macrophage-dependent STAT1-Driven Transcription in Atherosclerosis

This study investigates the role of STAT1-mediated IFN{gamma} signaling in atherosclerosis progression through multi-omics integration and analysis of human and mouse models of atherosclerotic lesions. By integrating ATAC-seq, ChIP-seq, and RNA-seq data from IFN{gamma}-treated bone marrow-derived macrophages, we identified 1139 STAT1-dependent integrative genes that show chromatin accessibility, differential epigenetic marks (H3K27ac, H3K4me1, H3K4me3), prominent transcription factor binding patterns (STAT1 and PU.1), and active transcription. These genes were also enriched for lipid metabolism and atherosclerosis-related pathways. We then validated our findings by tracing the expression of these genes in human atherosclerotic lesions and in ApoE-/- and LDLr-/-mouse models, revealing significant correlations with LDL cholesterol and diseased vessel traits. Single-cell RNA-seq of human and mouse atherosclerotic samples showed dynamic changes in macrophage subtypes, with foamy and tissue-resident macrophages displaying increased STAT1 activity. This comprehensive multi-omics approach provides new insights into the transcriptional regulation of atherosclerosis progression mediated by STAT1-PU.1 co-binding and IFN{gamma} signaling. Moreover, our data delineates a STAT1-dependent gene signature, highlighting the potential of these integrative genes as biomarkers and therapeutic targets in atherosclerosis.