No abstract

Production and secretion of insulin from the beta-cells of the pancreas is very crucial in maintaining normoglycaemia. This is achieved by tight regulation of insulin synthesis and exocytosis from the beta-cells in response to changes in blood glucose levels. The synthesis of insulin is regulated by blood glucose levels at the transcriptional and post-transcriptional levels. Although many transcription factors have been implicated in the regulation of insulin gene transcription, three beta-cell-specific transcriptional regulators, Pdx-1 (pancreatic and duodenal homeobox-1), NeuroD1 (neurogenic differentiation 1) and MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homologue A), have been demonstrated to play a crucial role in glucose induction of insulin gene transcription and pancreatic beta-cell function. These three transcription factors activate insulin gene expression in a co-ordinated and synergistic manner in response to increasing glucose levels. It has been shown that changes in glucose concentrations modulate the function of these beta-cell transcription factors at multiple levels. These include changes in expression levels, subcellular localization, DNA-binding activity, transactivation capability and interaction with other proteins. Furthermore, all three transcription factors are able to induce insulin gene expression when expressed in non-beta-cells, including liver and intestinal cells. The present review summarizes the recent findings on how glucose modulates the function of the beta-cell transcription factors Pdx-1, NeuroD1 and MafA, and thereby tightly regulates insulin synthesis in accordance with blood glucose levels.

SummaryTo maintain phenotypes of cell lineages cells must "remember" which genes were active before mitosis entry and transmit this information to their daughter cells so expression patterns can be faithfully re-established in G1, a phenomenon called gene bookmarking. However, during mitosis transcription ceases, most sequence-specific proteins dissociate from DNA, and the chromatin is tightly compacted, making it difficult to understand how gene activity "memory" is maintained through this stage of the cell cycle 1,2 . Gene bookmarking is associated with a lack of compaction of promoters of formerly active genes in mitotic cells, but how compaction of these regions is inhibited was unknown 3,4 . Here we show that during mitosis TATA-binding protein (TBP), which remains bound to DNA during mitosis, recruits PP2A and also interacts with condensin to allow efficient dephosphorylation/inactivation of condensin near these promoters to inhibit their compaction. Further, ChIP-on-chip data show that TBP is bound to many chromosomal sites during mitosis, and is higher in transcribed regions but low in regions containing pseudogenes and genes whose expression is tissue-restricted. These results suggest that TBP is involved not only in gene transcription during interphase but also in preserving the memory of gene activity through mitosis to daughter cells.The results of a number of studies suggest that the promoters of genes which are active prior to entry into mitosis are marked by the binding of some factor, that this factor remains associated with the promoter throughout this stage of the cell cycle, and that it somehow prevents compaction of these regions so that the transcriptional machinery can be reassembled on them in G1, thereby transmitting memory of gene expression patterns 5,6 . Because of similarities with the way a bookmark holds a place in a book, this mechanism has been referred to as gene bookmarking, and the putative factors mediating this process termed molecular bookmarks. However, the identity of the factor or factors involved in this mechanism, and how they prevent compaction of these promoter regions, was not known.One candidate for this active gene bookmarking factor was TBP, based on data showing that TBP remains associated with chromosomal DNA even during mitosis, but only with promoters of genes that had been active prior to entry into mitosis 7-9 . In a previous study we identified a mechanism for gene-selective bookmarking in which a factor called HSF2 binds the hsp70 promoter during mitosis and prevents its compaction by interacting with condensin and also recruiting the phosphatase PP2A to dephosphorylate and inactivate these nearby condensin complexes 10 . In this study we sought to test whether TBP functions as a general bookmarkingCorrespondence and requests for materials should be addressed to K.D.S (kdsarge@uky.edu). Author Information The authors declare no competing financial interests. factor for active gene promoters and, if so, whether there is any similarity between the mechanism...

MafA is a basic leucine zipper transcription factor that regulates gene expression in both the neuroretina and pancreas. Within the pancreas, MafA is exclusively expressed in the beta cells and is involved in insulin gene transcription, insulin secretion, and beta cell survival. The expression of the mafA gene within beta cells is known to increase in response to high glucose levels by an unknown mechanism. In this study, we demonstrate that pyruvate, which is produced by glycolysis from glucose, is not sufficient to induce mafA gene expression compared with high glucose. This suggests that the signal for MafA induction is independent of ATP levels and that a metabolic event occurring upstream of pyruvate production leads to the induction of MafA.