Mining the transcriptome of target tissues of autoimmune and degenerative pancreatic β-cell and brain diseases to discover therapies

Target tissues of autoimmune and degenerative diseases show signals of inflammation. We used publicly available RNA-seq data to study whether pancreatic β-cells in type 1 and type 2 diabetes and neuronal tissue in multiple sclerosis and Alzheimer's disease share inflammatory gene signatures. We observed concordantly upregulated genes in pairwise diseases, many of them related to signaling by interleukins and interferons. We next mined these signatures to identify therapies that could be re-purposed/shared among the diseases and identified the bromodomain inhibitors as potential perturbagens to revert the transcriptional signatures. We experimentally confirmed in human β-cells that bromodomain inhibitors I-BET151 and GSK046 prevent the deleterious effects of the pro-inflammatory cytokines interleukin-1β and interferon-γ and at least some of the effects of the metabolic stressor palmitate. These results demonstrate that key inflammation-induced molecular mechanisms are shared between β-cells and brain in autoimmune and degenerative diseases and that these signatures can be mined for drug discovery.

 

Comments:

That's an interesting study! It seems like you used publicly available RNA-seq data to investigate the inflammatory gene signatures in pancreatic β-cells in type 1 and type 2 diabetes, as well as neuronal tissue in multiple sclerosis and Alzheimer's disease. By comparing the gene expression profiles, you found concordantly upregulated genes that are related to signaling by interleukins and interferons, indicating shared molecular mechanisms in these diseases.

Building upon these findings, you further analyzed the gene signatures to identify potential therapeutic options that could be repurposed or shared among these diseases. One class of compounds that caught your attention were bromodomain inhibitors. These inhibitors have shown promise in reversing the transcriptional signatures associated with inflammation.

To validate this potential therapeutic approach, you conducted experiments using human β-cells and tested two bromodomain inhibitors, namely I-BET151 and GSK046. The results demonstrated that these inhibitors were able to prevent the deleterious effects of the pro-inflammatory cytokines interleukin-1β and interferon-γ, as well as some of the effects induced by the metabolic stressor palmitate.

Overall, your study suggests that there are shared inflammatory molecular mechanisms between β-cells in diabetes and neuronal tissue in multiple sclerosis and Alzheimer's disease. Furthermore, you highlight the potential of using these shared signatures for drug discovery, with bromodomain inhibitors showing promise as therapeutic candidates.

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S9684	GSK046 (iBET-BD2)	GSK046 (iBET-BD2) is a selective and orally active inhibitor of BET (bromodomain and extraterminal domain) with IC50 of 264 nM, 98 nM, 49 nM and 214 nM for BRD2BD2, BRD3BD2, BRD4BD2 and BRDTBD2, respectively. GSK046 exhibits immunomodulatory activity.

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