Two new members of an E2F subfamily, E2F7 and E2F8, were recently identified after our studies were performed, and like E2F4 and 5, act as repressors of E2F-induced gene expression and mitotic progression. Moreover, DUX4 interacts with DUX4c which, in turn, makes contact with FRG1 and FRG2. In normal cells, this S/MAR may constrain the flexibility of the region by anchoring it to the nuclear matrix, thus restricting interactions of adjacent Nitromide sequences in the three dimensional nuclear space. This could Ursolic-acid particularly affect the 4qA/B marker which is separated from neighbor genes by the S/MAR. In the present 3C experiments, no interactions were detected that involved FR-MAR. This should not be surprising since previous 3C studies have already stressed that S/MARs appear to interact only with other SMARs. We propose that IRE1a hyperactivation by chronic high glucose results in selective degradation of insulin mRNA, leading to glucose toxicity. It has been shown that insulin mRNA degrades rapidly under ER stress conditions in pancreatic b-cells. However, the precise mechanism whereby IRE1-mediated insulin mRNA degradation occurs is unclear. The reduction of insulin mRNA under ER stress conditions may be initiated by direct endonucleolytic cleavage by the nuclease domain of IRE1, ultimately leading to degradation of the insulin message. Alternatively, IRE1 may function in the activation or recruitment of additional ribonucleases that can degrade insulin messages. It is also possible that IRE1 signaling may somehow initiate insulin gene-specific transcriptional stalling. Regardless of the precise mechanism, our data show that IRE1a, a central component of ER stress signaling, has an essential function in the reduction of insulin mRNA. Numerous studies have implicated PDX-1 and MafA, two transcription factors that are important for insulin gene transcription, in the defective insulin gene expression in b-cells caused by chronic exposure to supraphysiologic concentrations of glucose.This JNK activation suppresses PDX-1 binding to the insulin promoter and reduces insulin gene expression. We have shown previously that in mammalian cells ER stress signaling activates JNK through IRE1. Thus, hyperactivation of IRE1a by chronic high glucose may suppress insulin gene expression partially through JNK-mediated PDX-1 inactivation.