Abstract
Type 1 diabetes (T1D) results from the progressive loss of pancreatic beta cells as a result of autoimmune destruction. We recently reported that during the natural history of T1D in humans and the female nonobese diabetic (NOD) mouse model, beta cells acquire a senescence-associated secretory phenotype (SASP) that is a major driver of disease onset and progression, but the mechanisms that activate SASP in beta cells were not explored. Here, we show that the SASP in islet cells is transcriptionally controlled by Bromodomain ExtraTerminal (BET) proteins, including Bromodomain containing protein 4 (BRD4). A chromatin analysis of key beta cell SASP genes in NOD islets revealed binding of BRD4 at active regulatory regions. BET protein inhibition in NOD islets diminished not only the transcriptional activation and secretion of SASP factors, but also the non-cell autonomous activity. BET protein inhibition also decreased the extent of SASP induction in human islets exposed to DNA damage. The BET protein inhibitor iBET-762 prevented diabetes in NOD mice and also attenuated SASP in islet cells in vivo. Taken together, our findings support a crucial role for BET proteins in the activation of the SASP transcriptional program in islet cells. These studies suggest avenues for preventing T1D by transcriptional inhibition of SASP.
Highlights
Type 1 diabetes (T1D) is a chronic metabolic disease of insulin deficiency caused by an organ-specific autoimmune disorder that leads to progressive loss of pancreatic beta cells
This revealed that Bromodomain containing protein 4 (BRD4) was enriched at the same regulatory regions of Mmp2 and Il6 that harbored H3K27 acetylation (H3K27ac), and treatment of islets with the potent small molecule Bromodomain ExtraTerminal (BET) inhibitor iBET-762 disrupted its binding at these sites (Figure 1c)
Our findings indicate that in nonobese diabetic (NOD) mice, the protection afforded by BET inhibitors against diabetes involves attenuation of senescence-associated secretory phenotype (SASP)
Summary
Type 1 diabetes (T1D) is a chronic metabolic disease of insulin deficiency caused by an organ-specific autoimmune disorder that leads to progressive loss of pancreatic beta cells. Selective ablation of senescent beta cells with small molecule senolytic compounds targeting Bcl-2 prevented T1D in the nonobese diabetic (NOD) mouse model by halting the autoimmune destruction process and preserving beta cell mass [3] These results demonstrate a causal role for SASP beta cells in the pathogenesis of T1D; the mechanisms of SASP activation in beta cells have not been determined. Recent efforts have revealed a growing list of transcription factors, chromatin architectural proteins, and modifiers that collaborate to orchestrate the activation of SASP genes, leading to the development of the secretory phenotype These include factors such as ATM, macroH2A1, HMGB2, MLL1, BRD4, NF-κB, CEBPβ, Mitf, and PARP-1, and inhibition or depletion of these factors in senescent cells reduces SASP gene activation and subsequent protein secretion [5,8,9,10,12,13]. Owing to the ability of accumulated SASP cells to profoundly alter tissue microenvironments and disrupt normal processes [14,15], pharmacological approaches to inhibit SASP at the transcriptional level could prove useful for mitigating the effects of senescent beta cells in T1D
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