학술논문
Deficiency of lncRNA MERRICALabrogates macrophage chemotaxis and diabetes-associated atherosclerosis
Document Type
Article
Author
Chen, Jingshu; Jamaiyar, Anurag; Wu, Winona; Hu, Yi; Zhuang, Rulin; Sausen, Grasiele; Cheng, Henry S.; de Oliveira Vaz, Camila; Pérez-Cremades, Daniel; Tzani, Aspasia; McCoy, Michael G.; Assa, Carmel; Eley, Samuel; Randhawa, Vinay; Lee, Kwangwoon; Plutzky, Jorge; Hamburg, Naomi M.; Sabatine, Marc S.; Feinberg, Mark W.
Source
Cell Reports; March 2024, Vol. 43 Issue: 3
Subject
Language
ISSN
22111247
Abstract
Diabetes-associated atherosclerosis involves excessive immune cell recruitment and plaque formation. However, the mechanisms remain poorly understood. Transcriptomic analysis of the aortic intima in Ldlr−/−mice on a high-fat, high-sucrose-containing (HFSC) diet identifies a macrophage-enriched nuclear long noncoding RNA (lncRNA), MERRICAL(macrophage-enriched lncRNA regulates inflammation, chemotaxis, and atherosclerosis). MERRICALexpression increases by 249% in intimal lesions during progression. lncRNA-mRNA pair genomic mapping reveals that MERRICALpositively correlates with the chemokines Ccl3 and Ccl4. MERRICAL-deficient macrophages exhibit lower Ccl3 and Ccl4 expression, chemotaxis, and inflammatory responses. Mechanistically, MERRICALguides the WDR5-MLL1 complex to activate CCL3 and CCL4 transcription via H3K4me3 modification. MERRICALdeficiency in HFSC diet-fed Ldlr−/−mice reduces lesion formation by 74% in the aortic sinus and 86% in the descending aorta by inhibiting leukocyte recruitment into the aortic wall and pro-inflammatory responses. These findings unveil a regulatory mechanism whereby a macrophage-enriched lncRNA potently inhibits chemotactic responses, alleviating lesion progression in diabetes.