{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T09:28:06Z","timestamp":1787304486270,"version":"build-2736575974"},"reference-count":109,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>R-loops, RNA-DNA hybrid structures with a displaced single-stranded DNA loop, are key regulators of transcriptional control, chromatin architecture, and genome stability and have emerging roles in inflammatory signaling. However, the relationship between R-loop abundance and strongly modulated inflammatory effector genes in metabolic inflammation and influenza virus infection remains underexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a locus-centric integrative analysis combining robust differentially expressed genes (DEGs) from multiple inflammatory and infection-related murine and human transcriptomic disease models with experimentally validated multi-cell R-loop annotations from the reference atlas RLoopBase. Our correlation framework evaluated the directional relationship between R-loop abundance and inflammatory gene expression rather than assuming disease-sample-matched R-loop measurements. We further analyzed R-loop regulatory proteins, NRF2-associated R-loop regulators, and overlaps between R-loop regulators and CRISPRi-identified mitochondrial and cellular reactive oxygen species (ROS) regulators.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In angiotensin II-infused apolipoprotein E-deficient (ApoE\u2212\/\u2212) mice, a model of abdominal aortic aneurysm (AAA), genomic regions encoding the top significantly upregulated genes exhibited significantly fewer R-loops than those encoding downregulated genes at days 14 and 28. Similarly, in atherosclerotic ApoE\u2212\/\u2212 mice fed a high-fat diet for 32 and 78 weeks, upregulated genes were associated with fewer R-loops than downregulated genes. Reduced R-loop abundance was also observed in genomic regions encoding the top significantly upregulated genes in liver tissues from patients with non-alcoholic steatohepatitis (NASH), as well as in monosodium urate (MSU)-stimulated lymphatic endothelial cells (LECs) and influenza virus-infected human umbilical vein endothelial cells (HUVECs). R-loop regulatory proteins upregulated during metabolic inflammation were enriched in immune and inflammatory pathways. NRF2 was identified as a regulator of 27 R-loop regulatory proteins, including 10 positively and 17 negatively regulated proteins. Furthermore, 54 R-loop regulatory proteins overlapped with CRISPRi-identified mitochondrial and cellular ROS regulators, suggesting potential reciprocal regulation between R-loop homeostasis and ROS signaling. Disease-associated changes in pro-ROS and anti-ROS R-loop regulatory proteins further linked R-loop regulation to inflammatory and oxidative stress pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings identify reduced R-loop abundance at genomic regions encoding strongly upregulated inflammatory genes as a shared feature across multiple models of metabolic inflammation and influenza virus infection. The results further suggest that immune-associated R-loop regulatory proteins and the NRF2\u2013ROS axis may contribute to R-loop remodeling during inflammatory disease. This integrative framework provides new insight into the potential role of R-loops and ROS-sensitive R-loop regulators in inflammatory and metabolic diseases and identifies candidate pathways for future mechanistic investigation and therapeutic targeting.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1782258","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T09:10:23Z","timestamp":1787303423000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Reduced R-loop abundance at proinflammatory loci: a shared epigenetic mechanism in inflammatory and metabolic diseases"],"prefix":"10.3389","volume":"13","author":[{"given":"William Y.","family":"Yang","sequence":"first","affiliation":[{"name":"School of Communication and Information, Rutgers University","place":["New Brunswick, NJ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma","family":"Saaoud","sequence":"additional","affiliation":[{"name":"Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keman","family":"Xu","sequence":"additional","affiliation":[{"name":"Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Ben Issa","sequence":"additional","affiliation":[{"name":"Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Lu","sequence":"additional","affiliation":[{"name":"Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Shao","sequence":"additional","affiliation":[{"name":"Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baosheng","family":"Han","sequence":"additional","affiliation":[{"name":"Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohua","family":"Jiang","sequence":"additional","affiliation":[{"name":"Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University","place":["Philadelphia, PA, United States"]},{"name":"Centers of Metabolic Disease Research and Thrombosis Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Centers of Metabolic Disease Research and Thrombosis Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laisel","family":"Martinez","sequence":"additional","affiliation":[{"name":"Department of Surgery, Leonard M. 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