Bromodomain-containing proteins have been linked to a number of inflammation-related disease states, including diabetes. The bromodomain family of epigenetic “reader” proteins interact with acylated lysine residues and lead to downstream regulation of gene transcription. Using drug-like chemical probes and targeted therapies, we dissect the roles of bromodomain-containing proteins in autoimmune diabetes onset and progression.
BET BROMODOMAIN INHIBITORS ATTENUATE TRASCRIPTION OF A SUBSET OF IL-1-INDUCED NF-KB TARGETS THAT PROMOTE INFLAMMATION IN β-CELLS
Inflammatory and autoimmune diseases often involve the activation of the transcription factor NF-κB, which stimulates the expression of genes that drive inflammation. BET proteins—epigenetic regulators that bind to modified histones—are involved by interaction with NF-κB. In Nord. et al (2025), we investigated how inhibiting BET proteins affects NF-κB activity in pancreatic β-cells, a key cell type involved in autoimmune diabetes. BET inhibitors selectively block the expression of NF-κB target genes that promote inflammation, while leaving genes that help maintain cell health and stress resistance largely unaffected. This suggests that BET inhibitors may provide a more targeted approach to reducing inflammation than direct NF-κB inhibition, which can sometimes worsen disease by suppressing beneficial genes. These findings help clarify how BET proteins influence gene expression in inflammatory settings and support their potential as therapeutic targets for autoimmune diseases like diabetes.
ZINC-CHELATING BET BROMODOMAIN INHIBITORS EQUALLY TARGET ISLET ENDOCRINE CELL TYPES
Inhibition of BET bromodomains is a novel potential strategy to prevent and treat diabetes mellitus. However, BET inhibitors have been shown to have numerous off-target systemic side effects. We synthesized a BET inhibitor expected to exploit the high zinc concentration in β cells to accumulate in β cells (Jones Lipinski et al, 2024). We show our inhibitor targeted pancreatic endocrine cells; however, it was less effective in immune cells. A control inhibitor showed the opposite effect. These findings help us understand how to target specific cells in diabetes treatment.
BET BROMODOMAIN INHIBITORS DISRUPT A BRD4-p65 INTERACTION
Chronic inflammation in pancreatic islets is a key driver of damage that leads to eventual onset of type I autoimmune diabetes. We investigated the ability of BET bromodomain inhibitors to reduce pancreatic β-cell responsiveness to the proinflammatory cytokine IL-1β (Nord et al 2022). Indeed, this inhibition attenuated inflammatory mediator gene NOS2, consistent with inhibition of NF-kB. We used selective inhibitors of the first and second bromodomains of BRD4 and showed only the first bromodomain was necessary for interaction of the NF-kB p65 subunit with BRD4. This is the first study illustrating the therapeutic potential for specific bromodomain-targeted inhibitors in autoimmune diabetes.
SELECTED REFERENCES
Nord JN, Makowski SJ, Sidlowski PFW, Bursch KL, Corbett JA, and Smith BC. BET bromodomain inhibitors attenuate transcription of a subset of IL-1-induced NF-kB targets that promote inflammation in β-cells. Journal of Biological Chemistry (2025). doi: 10.1016/j.jbc.2025.110358. PMID: 40505864.
Jones Lipinski RA, Stancill JS, Nuñez R, Wynia-Smith SL, Sprague DJ, Nord JA, Bird A, Corbett JA, Smith BC. Zinc-chelating BET bromodomain inhibitors equally target islet endocrine cell types. American Journal of Physiology: Regulatory, Integrative, and Comparative Physiology. (2024). doi: 10.1152/ajpregu.00259.2023. PMID: 38618911
Nord JA, Wynia-Smith SL, Gehant AL, Jones Lipinski RA, Naatz A, Rioja I, Kumar Prinja R, Corbett JA, Smith BC. N-terminal BET bromodomain inhibitors disrupt a BRD4-p65 interaction and reduce inducible nitric oxide synthase transcription in pancreatic ß-cells. Frontiers in Endocrinology. 2022. DOI: 10.3389/fendo.2022.923925.
