Recently, we identified thioredoxininteracting protein (TXNIP) as a mediator of glucotoxic beta cell death and discovered that lack of TXNIP protects against streptozotocinand obesity-induced diabetes by preventing beta cell apoptosis and preserving endogenous beta cell mass. TXNIP has therefore become an attractive target for diabetes therapy, but while we have found that TXNIP transcription is highly induced by glucose through a unique carbohydrate response element, the factors controlling this effect have remained unknown. Using transient transfection experiments we now show that overexpression of the carbohydrate response element-binding protein (ChREBP) transactivates the TXNIP promoter, while ChREBP knock down by siRNA completely blunts glucose-induced TXNIP transcription. Moreover, chromatin immunoprecipitation (ChIP) demonstrated that glucose leads to a dose and time-dependent recruitment of ChREBP to the TXNIP promoter in vivo in INS-1 beta cells as well as human islets. Furthermore, we found that the co-activator and histone acetyltransferase p300 co-immunoprecipitates with ChREBP and also binds to the TXNIP promoter in response to glucose. Interestingly, this is associated with specific acetylation of histone H4 and recruitment of RNA polymerase II as measured by ChIP.

Thus, with this study we have identified ChREBP as the transcription factor that mediates glucose-induced TXNIP expression in human islets and INS-1 beta cells and have characterized the chromatin modification associated with glucose-induced TXNIP transcription. In addition, the results reveal for the first time that ChREBP interacts with p300. This may explain how ChREBP induces H4