RBBP6 orchestrates diabetic endothelial dysfunction viadisrupting JUNB-centric chromatin topology

Diabetes mellitus, a chronic metabolic disease affecting over 536.6 million people globally, is closely associated with vascular endothelial dysfunction, an early hallmark of diabetic cardiovascular complications. This dysfunction is characterized by impaired endothelial nitric oxide synthase (eNOS) activity, reduced nitric oxide (NO) production, and diminished angiogenic capacity, ultimately contributing to tissue ischemia and complications such as diabetic nephropathy, coronary artery disease, and peripheral arterial disease. These complications significantly increase morbidity and mortality in diabetic patients. Endothelial cells, which regulate vascular development and function, rely on the coordinated activity of cis-regulatory elements, including enhancers and promoters, which are influenced by the three-dimensional (3D) genome architecture and transcription factors (TFs) such as AP-1, ETS, and GATA families. However, the mechanisms by which these TFs mediate enhancer-promoter interactions and how these interactions are altered under diabetic conditions remain poorly understood. To address this, we employed multi-omics profiling to map the 3D genome architecture in endothelial cells under hyperglycemic conditions in both diabetic mice and human vein endothelial cells. Our findings identify the disruption of JUNB-centric genome topology as a key feature of hyperglycemic endothelial cells. Moreover, we demonstrate that RBBP6 mediates ubiquitin-dependent degradation of JUNB, leading to changes in enhancer-promoter interactions. This study provides novel mechanistic insights into the chromatin 3D structural basis of endothelial dysfunction in diabetes and highlights the RBBP6-JUNB axis as a potential therapeutic target for preventing diabetic cardiovascular complications.