Atherosclerosis, a chronic arterial disease, is markedly accelerated in individuals with diabetes, accounting for a 2- to 4-fold increased risk of ischemic cardiovascular events. One of the hallmarks in this process involves the recruitment and accumulation of intimal macrophages, a process that is more pronounced in diabetes than without diabetes. The presence of pro-inflammatory macrophages facilitates the progression of atherosclerosis and impairs the ability of lesions to regress despite optimal medical therapy. Therefore, modulating monocyte/macrophage chemotaxis and accumulation in the vessel wall may provide a novel therapeutic approach to limit atherosclerotic progression and facilitate regression. Long non-coding RNAs (lncRNAs) are an emerging class of regulators of epigenetic modifiers, RNA, or protein-coding genes that has garnered attention for impacting diverse biological processes relevant to atherosclerosis. However, the identity and roles of specific lncRNAs within atherosclerotic lesions, especially in diabetes, are not well defined. Using RNA-Seq profiling to identify lncRNAs derived specifically from the atherosclerotic intima, we identify the lncRNA MERRICAL (Macrophage-Enriched lncRNA Regulates Inflammation, Chemotaxis, and AtheroscLerosis (MERRICAL). MERRICAL was the highest expressed lncRNA with a 249% increase concomitant with atherosclerotic progression under a high fat sucrose-containing (HFSC) diet and decreased with regression after a high cholesterol diet, but not after a HFSC diet. MERRICAL is a macrophage-enriched and nuclear-specific lncRNA. Our preliminary data demonstrate that delivery of inhibitors to MERRICAL in LDLR-/- HFSC-fed mice strongly reduced lesion size by 86%, independent of effects on circulating lipid profile, but rather by decreased macrophage accumulation in lesions. Preliminary studies show that MERRICAL in-cis regulates its neighboring genes Ccl3 and Ccl4 and macrophage chemotaxis mediated via interaction with a complex of the histone modifying enzyme H3K4me3. In addition, MERRICAL knockdown functions in-trans to regulate IL-1b-associated inflammasome signaling. These observations provide the central hypothesis that MERRICAL deficiency, via regulatory effects on H3K4me3 and macrophage chemokines and IL-b inflammasome signaling, reduces macrophage chemotaxis, lesional macrophage inflammatory signaling, and suppresses diabetes-associated atherosclerosis. To address this further, in Aim1 we examine the role of MERRICAL and the in-cis regulation of CCL3/CCL4 in macrophage chemotaxis and in-trans regulation of IL- 1b-associated inflammatory signaling; in Aim2, we assess how alterations of MERRICAL expression affects recruitment of lesional macrophages on lesion progression and regression in vivo; and in Aim3, we examine the role of the MERRICAL-H3K4me3 signaling axis in human cells and atherosclerotic lesions. Our studies will address a major gap in our understanding of lncRNAs in atherosclerosis an...