The Pancreatic Duodenal Homeobox-1 Protein (Pdx-1) Interacts with Histone Deacetylases Hdac-1 and Hdac-2 on Low Levels of Glucose

We have previously demonstrated that high concentrations of glucose stimulate insulin gene expression by causing hyperacetylation of histone H4 at the insulin gene promoter. Furthermore, we have shown that the glucose-mediated hyperacetylation of histone H4 depends on the recruitment of the histone acetyltransferase p300 by the beta cell-specific transcription factor Pdx-1. In this study, we demonstrate that the histone deacetylases Hdac-1 and Hdac-2 are rapidly recruited to the insulin promoter in the mouse insulinoma cell line MIN6 when cells are switched from high to low glucose media. Moreover, we demonstrate that the beta cell-specific homeodomain protein Pdx-1 interacts with histone deacetylases Hdac-1 and Hdac-2 at low levels of glucose. In vitro studies indicate that the interaction between Pdx-1 and Hdac-1 or Hdac-2 is direct and requires the C terminus of Pdx-1. Treatment of MIN6 cells with okadaic acid, which inhibits the activity of protein phosphatases, abolishes the interaction of Pdx-1 with Hdac-1 and Hdac-2 on low levels of glucose, suggesting the requirement of a dephosphorylation event for this interaction to occur. These data indicate that insulin gene expression is decreased on low levels of glucose by recruitment of Hdac-1 and Hdac-2 to the insulin promoter by the transcription factor Pdx-1. We have previously demonstrated that high concentrations of glucose stimulate insulin gene expression by causing hyperacetylation of histone H4 at the insulin gene promoter. Furthermore, we have shown that the glucose-mediated hyperacetylation of histone H4 depends on the recruitment of the histone acetyltransferase p300 by the beta cell-specific transcription factor Pdx-1. In this study, we demonstrate that the histone deacetylases Hdac-1 and Hdac-2 are rapidly recruited to the insulin promoter in the mouse insulinoma cell line MIN6 when cells are switched from high to low glucose media. Moreover, we demonstrate that the beta cell-specific homeodomain protein Pdx-1 interacts with histone deacetylases Hdac-1 and Hdac-2 at low levels of glucose. In vitro studies indicate that the interaction between Pdx-1 and Hdac-1 or Hdac-2 is direct and requires the C terminus of Pdx-1. Treatment of MIN6 cells with okadaic acid, which inhibits the activity of protein phosphatases, abolishes the interaction of Pdx-1 with Hdac-1 and Hdac-2 on low levels of glucose, suggesting the requirement of a dephosphorylation event for this interaction to occur. These data indicate that insulin gene expression is decreased on low levels of glucose by recruitment of Hdac-1 and Hdac-2 to the insulin promoter by the transcription factor Pdx-1. The production and secretion of insulin from pancreatic beta cells is regulated by changes in blood glucose levels, and defects in this regulatory process result in metabolic disorders such as diabetes. Insulin gene expression is up-regulated by increases in glucose concentration and involves several transcription factors including Pdx-1, 1The abbreviations used are: Pdx-1, pancreatic duodenal homeobox-1; MIN6, mouse insulinoma 6; Hdac-1/2, histone deacetylase 1/2; ChIP, chromatin immunoprecipitation; GST, glutathione S-transferase; NTA, nitrilotriacetic acid; PBS, phosphate-buffered saline; Ct, threshold cycle; HEK, human embryonic kidney cell; CREB, cAMP response element-binding protein; CBP, CREB-binding protein. 1The abbreviations used are: Pdx-1, pancreatic duodenal homeobox-1; MIN6, mouse insulinoma 6; Hdac-1/2, histone deacetylase 1/2; ChIP, chromatin immunoprecipitation; GST, glutathione S-transferase; NTA, nitrilotriacetic acid; PBS, phosphate-buffered saline; Ct, threshold cycle; HEK, human embryonic kidney cell; CREB, cAMP response element-binding protein; CBP, CREB-binding protein. MafA, and NeuroD (1Melloul D. Ann. N. Y. Acad. 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Expression of Pdx-1 in the NES2Y cell line or in islets of the type 2 diabetes model Psammomys obesus, which are defective for expression of Pdx-1, restores their ability to stimulate insulin gene expression in response to increases in glucose levels (9Macfarlane W.M. Shepherd R.M. Cosgrove K.E. James R.F. Dunne M.J. Docherty K. Diabetes. 2000; 49: 418-423Crossref PubMed Scopus (61) Google Scholar, 10Leibowitz G. Melloul D. Yuli M. Gross D.J. Apelqvist A. Edlund H. Cerasi E. Kaiser N. Diabetes. 2001; 50: S138-S139Crossref PubMed Google Scholar). Mutations in Pdx-1 have also been associated with the MODY4 locus (11Stoffers D.A. Stanojevic V. Habener J.F. J. Clin. Investig. 1998; 102: 232-241Crossref PubMed Scopus (156) Google Scholar, 12Stoffers D.A. Ferrer J. Clarke W.L. Habener J.F. Nat. Genet. 1997; 17: 138-139Crossref PubMed Scopus (8) Google Scholar), which is a subtype of type 2 diabetes. Modification of the N-terminal tails of histones by acetylation has been implicated in regulation of gene expression (13Strahl B.D. Allis C.D. Nature. 2000; 403: 41-45Crossref PubMed Scopus (6448) Google Scholar). In general, hyperacetylation of histone tails is associated with increased gene expression, while hypoacetylation is associated with repression of transcription or silencing (14Berger S.L. Curr. Opin. Genet. Dev. 2002; 12: 142-148Crossref PubMed Scopus (973) Google Scholar). However, inhibition of histone deacetylase activity by treatment with trichostatin A leads to both activation and silencing of a subset of genes (15Van Lint C. Emiliani S. Verdin E. Gene Expr. 1996; 5: 245-253PubMed Google Scholar). Several histone acetyltransferases as well as histone deacetylases have been cloned to date and implicated in regulation of gene expression (16Goodman R.H. Smolik S. Genes Dev. 2000; 14: 1553-1577PubMed Google Scholar, 17Ng H.H. Bird A. Trends Biochem. Sci. 2000; 25: 121-126Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar). A number of transcription factors, including NFkB and the muscle-specific transcription factor MEF2 have been shown to interact with both the histone acetyltransferases and decacetylases (18Zhong H. Voll R.E. Ghosh S. Mol. Cell. 1998; 1: 661-671Abstract Full Text Full Text PDF PubMed Scopus (1017) Google Scholar, 19Zhong H. May M.J. Jimi E. Ghosh S. Mol. Cell. 2002; 9: 625-636Abstract Full Text Full Text PDF PubMed Scopus (800) Google Scholar, 20McKinsey T.A. Zhang C.L. Lu J. Olson E.N. Nature. 2000; 408: 106-111Crossref PubMed Scopus (860) Google Scholar, 21Chan J.K. Sun L. Yang X.J. Zhu G. Wu Z. J. Biol. Chem. 2003; 278: 23515-23521Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). However, the exact mechanisms that determine the interaction of a specific transcription factor with various histone-modifying enzymes are for the most part unknown. Histone deacetylases are divided into three different classes based on their homology, and Hdac-1 and Hdac-2 belong to the class I histone deacetylases together with Hdac-3 and Hdac-8 (17Ng H.H. Bird A. Trends Biochem. Sci. 2000; 25: 121-126Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar, 22Cress W.D. Seto E. J. Cell. Physiol. 2000; 184: 1-16Crossref PubMed Scopus (573) Google Scholar). The class I histone deacetylases are ∼400–500 amino acid long and localized primarily to the nucleus. Histone deacetylases exist as large protein complexes, and Hdac-1/Hdac-2 have been shown to associate with co-repressor complexes Sin3A and Mi-2/NuRD (17Ng H.H. Bird A. Trends Biochem. Sci. 2000; 25: 121-126Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar, 22Cress W.D. Seto E. J. Cell. Physiol. 2000; 184: 1-16Crossref PubMed Scopus (573) Google Scholar, 23Heinzel T. Lavinsky R.M. Mullen T.M. Soderstrom M. Laherty C.D. Torchia J. Yang W.M. Brard G. Ngo S.D. Davie J.R. Seto E. Eisenman R.N. Rose D.W. Glass C.K. Rosenfeld M.G. Nature. 1997; 387: 43-48Crossref PubMed Scopus (1077) Google Scholar). The presence of histone deacetylases in distinctive complexes with different transcription factors appears to contribute to their diverse biological activities. Multiple studies indicate that the histone deacetylase Hdac-1 and Hdac-2 contain several different post-translational modifications, including phosphorylation and sumoylation (24Galasinski S.C. Resing K.A. Goodrich J.A. Ahn N.G. J. Biol. Chem. 2002; 277: 19618-19626Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 25David G. Neptune M.A. DePinho R.A. J. Biol. Chem. 2002; 277: 23658-23663Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar). However, the exact role of these post-translational modifications in regulating the function and activity of these enzymes, and the tissue specificity of these modifications is unknown. The beta cell-specific transcription factor Pdx-1 has been previously shown to interact with the histone acetyltransferases p300 and CBP, and this interaction has been demonstrated to be important for insulin gene expression (26Asahara H. Dutta S. Kao H-Y. Evans R.M. Montminy M. Mol. Cell. Biol. 1999; 19: 8219-8225Crossref PubMed Scopus (129) Google Scholar, 27Qiu Y. Guo M. Huang S. Stein R. Mol. Cell. Biol. 2002; 22: 412-420Crossref PubMed Scopus (150) Google Scholar, 28Mosley A.L. Corbett J.A. Özcan S. Mol. Endocrinol. 2004; 18: 2279-2290Crossref PubMed Scopus (95) Google Scholar). We have recently demonstrated that induction of insulin gene expression by high concentrations of glucose involves the hyperacetylation of histone H4 at the insulin gene promoter (29Mosley A.L. Özcan S. J. Biol. Chem. 2003; 278: 19660-19666Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). At low levels of glucose, insulin gene expression is down-regulated, which correlates with deacetylation of histone H4 at the insulin promoter. In this report, we demonstrate that the beta cell-specific transcription factor Pdx-1 interacts with histone deacetylases Hdac-1 and Hdac-2 at low levels of glucose. Furthermore, Hdac-1 and Hdac-2 are associated with the insulin promoter only when glucose levels are low. Therefore, it is likely that Pdx-1 recruits Hdac-1 and Hdac-2 to the insulin gene promoter to cause deacetylation of histone H4 and down-regulation of insulin gene expression when glucose levels are low. Cell Culture—Mouse insulinoma-6 (MIN6) cells of passage 22 through in glucose, 2 and J. K. E. H. T. Y. Y. K. Endocrinol. PubMed Scopus Google Scholar). the glucose regulation MIN6 cells in with glucose and three with and to or glucose for 2 as previously (29Mosley A.L. Özcan S. J. Biol. Chem. 2003; 278: 19660-19666Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, J. 2002; PubMed Scopus Google Scholar). The used for in Hdac-1 Hdac-2 and p300 from histone H4 from and Pdx-1 from on a in a as previously (29Mosley A.L. Özcan S. J. Biol. Chem. 2003; 278: 19660-19666Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). The for different and by the The used are and for the mouse insulin I promoter to at three for The with the to the with the The a The the and their by of histone and Pdx-1 with the mouse insulin I promoter in cells with or glucose the and with to the The used to the insulin promoter are and used at a concentration of on a to the The threshold for as the at which the that the of data as previously James J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, J.F. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). to the of the various with the insulin I a for by the for the from the with the as The for the with specific from the of with as to the is to a in in from three A for to that the with the presence of a of Cell and cell from MIN6 cells with or glucose as previously for of the cells A.L. Corbett J.A. Özcan S. Mol. Endocrinol. 2004; 18: 2279-2290Crossref PubMed Scopus (95) Google Scholar). The used in the in and of by the with of and with Pdx-1, Hdac-1 Hdac-2 and at by with protein for The in of and in or mouse used as a for the Expression and of and and by of W.M. Sun Davie J.R. Seto E. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). expression and of cells the various in of at to a of at and expression of the with for the cells by the cell in of and and by passage through a The cell at for 2 and the on to and with of the The protein from the with a at and at in The and expressed the The used and 2 a and by with a at and at The 2 The protein concentration and by the on together with a and by with In of with for the with 2 of the and with at for The with and the from the by for in The the by of with these the also of Pdx-1 or which the N-terminal amino the activation the as previously A.L. Özcan S. Mol. 2003; Google Scholar, S. J. Acad. Sci. S. A. 1998; PubMed Scopus Google Scholar). the Pdx-1 or the mouse Pdx-1 or Pdx-1 the by and into the with a as The with to Pdx-1 or to and into the of the S. J. Acad. Sci. S. A. 1998; PubMed Scopus Google Scholar). The into E. cells with the in the into E. cells and the and used to cells to the The cell used for by several of of MIN6 cells with a of of a to the A.L. Özcan S. Mol. 2003; Google Scholar). of Histone deacetylase activity associated with Pdx-1 or the Pdx-1 protein by of MIN6 cell with 2 of mouse or of of protein the on a at for The protein by and with of and in of Histone deacetylase activity the activity the with in of for at and a at and at M. Biochem. 2002; PubMed Scopus Google Scholar). of a deacetylation of a histone when with M. Biochem. 2002; PubMed Scopus Google Scholar). The Histone Hdac-1 and Hdac-2 to the Insulin Gene in the of of have previously shown that high concentrations of glucose stimulate insulin gene expression by causing the hyperacetylation of histone H4 at the insulin gene promoter A.L. Corbett J.A. Özcan S. Mol. Endocrinol. 2004; 18: 2279-2290Crossref PubMed Scopus (95) Google Scholar, A.L. Özcan S. J. Biol. Chem. 2003; 278: 19660-19666Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). to low concentrations of glucose the deacetylation of histone which with decreased insulin gene Treatment with trichostatin which inhibits histone deacetylase to increased histone H4 acetylation and insulin gene expression at low concentrations of glucose (29Mosley A.L. Özcan S. J. Biol. Chem. 2003; 278: 19660-19666Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). These data a role for histone deacetylases in insulin gene expression at low glucose. this we the recruitment of the Hdac-1 and Hdac-2 and the histone acetyltransferase p300 to the insulin gene promoter the in the mouse insulinoma cell line MIN6 with low concentrations of glucose. this the MIN6 cells on high glucose and to glucose for and used for with or p300 We that at the histone acetyltransferase p300 at the insulin gene promoter as previously A.L. Corbett J.A. Özcan S. Mol. Endocrinol. 2004; 18: 2279-2290Crossref PubMed Scopus (95) Google Scholar). of to low glucose the of p300 at the insulin promoter decreased The of Hdac-1 and Hdac-2 with the insulin gene promoter only to glucose The recruitment of Hdac-1 and Hdac-2 to the insulin promoter by the mouse insulin I promoter and with the deacetylation of histone H4 Hdac-1 and Hdac-2 are recruited to the insulin promoter only in the presence of low levels of glucose, we the of these regulated by glucose. from MIN6 cells with or glucose used for with Hdac-1 or Hdac-2 and We that the levels of Hdac-1 or Hdac-2 on and glucose Pdx-1 with Hdac-1 and Hdac-2 in a in the beta cell-specific transcription factor Pdx-1 is the in glucose regulation of insulin gene we Pdx-1 is to interact with the histone deacetylases Hdac-1 and Hdac-2 in in a by from MIN6 cells with or glucose and used in with Pdx-1 or of from Pdx-1 with Hdac-1 or Hdac-2 that these with Pdx-1 The interaction of Pdx-1 with Hdac-1 and Hdac-2 in the presence of low concentrations of glucose. in with Hdac-1 and Hdac-2 and by with Pdx-1 Pdx-1 interacts with Hdac-1 and Hdac-2 mainly on low levels glucose, we the in of Pdx-1 with the insulin promoter on low or high concentrations of glucose the with Pdx-1 previously Pdx-1 is to the insulin promoter both low and high levels of glucose A.L. Corbett J.A. Özcan S. Mol. Endocrinol. 2004; 18: 2279-2290Crossref PubMed Scopus (95) Google Scholar). However, the in of Pdx-1 to the insulin promoter increased by on with glucose in We when used for or with that the promoter in Pdx-1 or The promoter as a Pdx-1 to this promoter in Pdx-1 with Hdac-1 and Hdac-2 in to determine the interaction between Pdx-1 and the histone deacetylases Hdac-1 and Hdac-2 and and from of with concentrations of or as by or glutathione to the Pdx-1 to interact with both Hdac-1 and Hdac-2 in vitro and interaction between Pdx-1 and These data indicate that Pdx-1 interacts with the histone deacetylase Hdac-1 and Hdac-2 Hdac-1 and Hdac-2 with a of to determine the interaction of Pdx-1 with Hdac-1 and Hdac-2 requires the activation of Pdx-1, MIN6 cells with which of Pdx-1 that the amino the activation protein as a it with the Pdx-1 for to the insulin promoter is to The Pdx-1 protein with a human at the C the interaction of with Hdac-1 and from MIN6 cells with or glucose with human or Hdac-2 of with that to interact with Hdac-1 and Hdac-2 of the glucose concentration with the Pdx-1 which interaction mainly on low glucose the Pdx-1, to interact with Hdac-1 and Hdac-2 in in vitro In of the histone deacetylase activity associated with the Pdx-1 in cells with glucose Moreover, in MIN6 cells the Pdx-1 histone deacetylase activity associated with on glucose and that with the Pdx-1 The histone deacetylase activity associated with and Pdx-1 protein by with the N-terminal Pdx-1 in and The between Pdx-1 and Hdac-1 or Hdac-2 by a data indicate that a phosphorylation event the interaction of Pdx-1 with the histone acetyltransferase p300 in response to high concentrations of glucose and that treatment with okadaic acid a interaction of Pdx-1 with p300 A.L. Corbett J.A. Özcan S. Mol. Endocrinol. 2004; 18: 2279-2290Crossref PubMed Scopus (95) Google Scholar). on these data we that high concentrations of glucose the interaction of Pdx-1 with Hdac-1 and the of Pdx-1 with the that a dephosphorylation event is required to the interaction of Pdx-1 with Hdac-1/2, we MIN6 cells in low in the presence or of the okadaic of the the used to Pdx-1 and the presence of Hdac-1 or Hdac-2 in Pdx-1 by Hdac-1 or The interaction between Pdx-1 and by treatment with okadaic acid suggesting the that a dephosphorylation event is required to the interaction of Pdx-1 with Hdac-1 and data indicate that Pdx-1 changes in response to different concentrations of glucose A.L. Corbett J.A. Özcan S. Mol. Endocrinol. 2004; 18: 2279-2290Crossref PubMed Scopus (95) Google Scholar, J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Docherty K. Diabetes. 2001; 50: PubMed Scopus Google Scholar). At high levels of glucose, Pdx-1 is localized mainly to the and and in response to low glucose it to the Hdac-1 and Hdac-2 to be localized to the in the MIN6 cell line of the glucose concentration Modification of N-terminal tails of histones by acetylation has been with increased gene expression (13Strahl B.D. Allis C.D. Nature. 2000; 403: 41-45Crossref PubMed Scopus (6448) Google Scholar, S.L. Curr. Opin. Genet. Dev. 2002; 12: 142-148Crossref PubMed Scopus (973) Google Scholar). We have previously shown that glucose insulin gene expression by causing hyperacetylation of histone H4 at the insulin gene promoter (29Mosley A.L. Özcan S. J. Biol. Chem. 2003; 278: 19660-19666Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). Furthermore, we that the hyperacetylation of histone H4 at the insulin promoter by high glucose requires the recruitment of the histone acetyltransferase p300 interaction with the beta cell specific transcription factor Pdx-1 A.L. Corbett J.A. Özcan S. Mol. Endocrinol. 2004; 18: 2279-2290Crossref PubMed Scopus (95) Google Scholar). In this report, we demonstrate that Pdx-1 interacts also with the histone deacetylases Hdac-1 and Hdac-2 in mainly at low levels of glucose. The interaction of Pdx-1 with Hdac-1 and Hdac-2 is by treatment with okadaic acid, which inhibits protein such as and James J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). In we that Hdac-1 and Hdac-2 are recruited to the insulin promoter when cells are switched from high to low levels of glucose and be for the hypoacetylation of histone H4 at the insulin promoter. on these and we that at high concentrations of glucose, a phosphorylation event the interaction of Pdx-1 with the histone acetyltransferase which recruited to the insulin promoter and hyperacetylation of histone H4 at this promoter to of insulin gene transcription At low levels of glucose, a dephosphorylation event Pdx-1 to from p300 and to interact with the histone deacetylases Hdac-1 and of Hdac-1 and Hdac-2 to the insulin promoter at low levels of glucose leads to hypoacetylation of histone in down-regulation of insulin gene expression with the that Pdx-1 in insulin gene expression low and high concentrations of glucose, Pdx-1 is associated with the insulin promoter in both However, the of Pdx-1 to the insulin promoter is increased in response to high glucose is that the of Pdx-1 with the insulin promoter is by interaction with the histone acetyltransferase the acetylation of histone H4 at the insulin promoter the of Pdx-1. Several transcription factors have been shown to interact with both histone acetyltransferases and deacetylases in a regulated The interaction of with Hdac-1 in cells the expression of muscle-specific genes S. A. L. V. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). the of with the histone acetyltransferases p300 and is important for V. Yang X.J. Y. L. A. Y. M. Mol. Cell. 1997; 1: Full Text Full Text PDF PubMed Scopus Google Scholar). The transcription factor response element-binding interacts with the histone deacetylases Hdac-1 G. E. H. S. S.D. Montminy M. Nat. Biol. 2003; PubMed Scopus Google as well as with the histone acetyltransferases and p300 when it is N. M. Montminy R.H. Nature. PubMed Scopus Google Scholar, J.R. R.H. Nature. 1994; PubMed Scopus Google Scholar). data indicate that the N-terminal activation of Pdx-1, which is required for interaction with the histone acetyltransferases p300 and (26Asahara H. Dutta S. Kao H-Y. Evans R.M. Montminy M. Mol. Cell. Biol. 1999; 19: 8219-8225Crossref PubMed Scopus (129) Google Scholar, 27Qiu Y. Guo M. Huang S. Stein R. Mol. Cell. Biol. 2002; 22: 412-420Crossref PubMed Scopus (150) Google Scholar), is for interaction with Hdac-1 and Hdac-2 in vitro as well as in several have been shown to interact with Pdx-1 N-terminal activation only protein has been to interact with Pdx-1 C terminus A. D.A. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar). it has been demonstrated that inhibits the ability of Pdx-1 to transcription A. D.A. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar). However, it is is in a with Pdx-1 and also to be is to interact with the histone deacetylases Treatment of MIN6 cells with okadaic acid, which inhibits the activity of the protein and the of Pdx-1 to A.L. Corbett J.A. Özcan S. Mol. Endocrinol. 2004; 18: 2279-2290Crossref PubMed Scopus (95) Google Scholar, J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Docherty K. Diabetes. 2001; 50: PubMed Scopus Google and also inhibits interaction with Hdac-1 and Hdac-2 on low levels of glucose. it is that the of Pdx-1 to is important for interaction with Hdac-1 and the of Pdx-1 to and interaction with Hdac-1 and Hdac-2 at low concentrations of glucose be Hdac-1 and Hdac-2 to be localized to the of the glucose concentration both the of Pdx-1 to and interaction with Hdac-1 and Hdac-2 at low levels of glucose requires a dephosphorylation is likely that Pdx-1 at high concentrations of glucose which it to interact with the histone acetyltransferase p300 to insulin gene expression At low concentrations of glucose, dephosphorylation of Pdx-1 cause from p300 and interaction with Hdac-1 and Hdac-2 to insulin gene expression In with this we that Pdx-1 is a Pdx-1 appears to be of glucose levels is likely that Pdx-1 at different on the concentration of glucose, which determine interaction with p300 or However, it is also that to low levels of glucose the dephosphorylation of Hdac-1 and which their interaction with Pdx-1. data indicate that Hdac-1 and Hdac-2 are by protein which the between Hdac-1 and Hdac-2 with the co-repressor (24Galasinski S.C. 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Biol. 2003; PubMed Scopus Google Scholar). okadaic acid is of it is that on low levels glucose, the interaction of Hdac-1 with Pdx-1 stimulate the dephosphorylation of Pdx-1 and interaction with the histone acetyltransferase shown for the transcription factor CREB, of Pdx-1 with Hdac-1 and or result in dephosphorylation of Pdx-1 and deacetylation of histone H4 at the insulin promoter at low levels of glucose. result in down-regulation of insulin gene expression at low concentrations of glucose.