{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:17:11Z","timestamp":1790997431024,"version":"4.1.0"},"reference-count":126,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Atherosclerosis is a chronic inflammatory disease of blood vessels, characterized by atherosclerotic lesions in large- and medium-sized arteries. IFN\u03b3 is a crucial mediator of atherosclerosis through activation of signal transducer and activator of transcription (STAT)1. Macrophages (M\u00d8), in different subtypes, play a central role in atherosclerosis, from early foam cell formation to advanced plaque development and potential rupture. Recent evidence in M\u00d8 supports a collaborative role of STAT1 with PU.1, in association with histone acetylation and methylation marks, in M\u00d8-specific IFN\u03b3-activated transcriptional responses. This study investigated the role of M\u00d8 STAT1-mediated signaling in atherosclerosis progression through multi-omics integration of IFN\u03b3-induced M\u00d8 and expression analysis in human and mouse atherosclerotic lesions. First, by integrating ATAC-seq, ChIP-seq, and RNA-seq data from IFN\u03b3-treated and untreated bone marrow-derived M\u00d8, we identified 1139 STAT1-dependent integrative genes. Active transcription of these genes was characterized by prominent promoter STAT1-PU.1 co-binding, increased histone methylation and acetylation and chromatin accessibility. Moreover, KEGG-analysis unraveled a strong connection to lipid metabolism and atherosclerosis-related pathways, whereas STARNET analysis identified high association with LDL cholesterol and diseased vessel traits. Using scRNA-seq data analysis of human carotid and coronary atherosclerotic lesions revealed dynamic changes of STAT1-dependent integrated genes in M\u00d8 subtypes, including foamy M\u00d8, monocytes, inflammatory M\u00d8, tissue resident M\u00d8 and conventional dendritic cells. Comparative M\u00d8-dependent expression analysis in aortic lesions from LDLr-\/- and ApoE-\/- high fat diet mouse models substantiated overlap between human and mouse atherosclerosis and identified 24 M\u00d8-specific commonly expressed STAT1-dependent integrated genes. Collectively, we provide detailed insights into M\u00d8-specific IFN\u03b3-activated transcriptional changes, mediated by STAT1-PU.1 co-binding and associated epigenetic changes, and offer the identification of new biomarkers and therapeutic targets in atherosclerosis. Moreover, we present a novel STAT1-dependent gene signature that could potentially serve to monitor M\u00d8-dependent plaque progression during human atherosclerotic disease.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1590953","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T05:47:52Z","timestamp":1750225672000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Integrative multi-omics analysis of IFN\u03b3-induced macrophages and atherosclerotic plaques reveals macrophage-dependent STAT1-driven transcription in atherosclerosis"],"prefix":"10.3389","volume":"16","author":[{"given":"Mahdi","family":"Eskandarian Boroujeni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Lopacinska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Antonczyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Kluzek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Wesoly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans A. 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