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

Reddy, M. A.; Bhattacharya, S.; Tanwar, V. S.; Malek, V.; Chen, Z.; Zhang, L.; Lanting, L.; Wu, X.; Grant, M. B.; Tompkins, J.; Chen, Z. B.; Natarajan, R.

doi:10.64898/2026.05.27.727961

bioRxiv · 10.64898/2026.05.27.727961

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

Reddy, M. A.·Bhattacharya, S.·Tanwar, V. S.·Malek, V.·Chen, Z.·Zhang, L.·Lanting, L.·Wu, X.·Grant, M. B.·Tompkins, J.·Chen, Z. B.·Natarajan, R.

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Abstract

Aberrant monocyte/macrophage activation in diabetes drives chronic inflammation and complications. While epigenetic mechanisms are implicated, the role of 3D-chromatin reorganization remains unclear. Using integrated multi-Omics, we profiled gene expression and 3D-chromatin architecture in human CD14+ monocyte-differentiated macrophages treated with high glucose + TNF- (HT) mimicking the diabetic milieu. HT induced inflammatory programs resembling those in diabetes, and dynamically altered chromatin accessibility, enhancer-promoter loops, transcriptionally active/inactive (A/B) compartments, and topologically associated domains. Inflammatory genes exhibited increased, whereas cell-cycle and metabolic genes showed reduced chromatin accessibility and enhancer-promoter interactions. These architectural changes facilitated the convergence of lineage-specific and signal-dependent transcription factors at enhancer-promoter loops, forming network hubs orchestrating pro-inflammatory responses. Similar enhancer-promoter interactions were observed in monocytes from individuals with diabetes. Perturbing chromatin interactions via CRISPR-interference targeting HT-induced enhancers suppressed inflammatory gene expression. Results from this first comprehensive enhancer connectome maps in macrophages under diabetic conditions reveal disease-associated rewiring of the 3D epigenome, highlighting epigenetic mechanisms as potential therapeutic targets. TeaserDiabetic conditions rewire 3D chromatin organization and enhancer-promoter interactions in human macrophages, promoting chronic inflammation.

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Reddy, M. A., Bhattacharya, S., Tanwar, V. S., Malek, V., Chen, Z., Zhang, L., Lanting, L., Wu, X., Grant, M. B., Tompkins, J., Chen, Z. B., Natarajan, R.. 2026-05-31. Epigenome Alterations and 3D Chromatin Architecture Remodeling in Inflammatory Macrophage Activation under Diabetic Conditions. https://doi.org/10.64898/2026.05.27.727961

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