Epigenome Alterations and 3D Chromatin Architecture Remodeling in Inflammatory Macrophage Activation under Diabetic...

Aberrant monocyte/macrophage activation in diabetes drives chronic inflammation and diabetic complications. Although epigenetic mechanisms are implicated in these processes, the contribution of three-dimensional (3D) chromatin reorganization remains unclear. Here, we use integrated multi-omics approaches to profile gene expression, chromatin accessibility and 3D chromatin architecture in human CD14⁺ monocyte-derived macrophages exposed to high glucose and TNF-α (HT), mimicking the diabetic milieu. HT induces inflammatory transcription programs that recapitulate those observed in diabetes and dynamically remodel chromatin accessibility, enhancer-promoter interactions, and topologically associated domains. Inflammatory genes exhibit increased chromatin accessibility, whereas cell cycle and metabolic genes display reduced accessibility and weakened enhancer-promoter interactions. These architectural changes promote the convergence of lineage-determining and signal-dependent transcription factors at enhancer-promoter loops, generating distinct regulatory hubs that orchestrate pro-inflammatory responses. Similar enhancer-promoter interactions are observed in peripheral blood derived monocytes from individuals with diabetes. Furthermore, perturbing chromatin interactions via CRISPR interference targeting HT-induced enhancers suppresses nearby CCL2 and other chemokine genes. Collectively, this first comprehensive enhancer connectome map of macrophages under diabetic conditions advances the field by revealing extensive disease-associated rewiring of the 3D epigenome, highlighting chromatin architecture and epigenetic mechanisms as potential therapeutic target for diabetes-associated inflammation.

In diabetes, high glucose (Glc) and inflammatory cytokines remodel macrophage 3D chromatin architecture and enhancer connectomes, altering enhancer-promoter interactions, facilitating the convergence of lineage-specific and signal-dependent transcription factors (such as NF-κB) that regulate inflammatory factors associated with macrophage activation. This can promote chronic inflammation and accelerate diabetic complications. Targeted enhancer editing strategies could enable new epigenetic therapies to mitigate chronic inflammatory diabetes complications.