title: PARP-1 and YY1 are important novel regulators of CXCL12 gene transcription in rat pancreatic beta cells.
abstract: Despite significant progress, the molecular mechanisms responsible for pancreatic beta cell depletion and development of diabetes remain poorly defined. At present, there is no preventive measure against diabetes. The positive impact of CXCL12 expression on the pancreatic beta cell prosurvival phenotype initiated this study. Our aim was to provide novel insight into the regulation of rat CXCL12 gene (Cxcl12) transcription. The roles of poly(ADP-ribose) polymerase-1 (PARP-1) and transcription factor Yin Yang 1 (YY1) in Cxcl12 transcription were studied by examining their in vitro and in vivo binding affinities for the Cxcl12 promoter in a pancreatic beta cell line by the electrophoretic mobility shift assay and chromatin immunoprecipitation. The regulatory activities of PARP-1 and YY1 were assessed in transfection experiments using a reporter vector with a Cxcl12 promoter sequence driving luciferase gene expression. Experimental evidence for PARP-1 and YY1 revealed their trans-acting potential, wherein PARP-1 displayed an inhibitory, and YY1 a strong activating effect on Cxcl12 transcription. Streptozotocin (STZ)-induced general toxicity in pancreatic beta cells was followed by changes in Cxcl12 promoter regulation. PARP-1 binding to the Cxcl12 promoter during basal and in STZ-compromised conditions led us to conclude that PARP-1 regulates constitutive Cxcl12 expression. During the early stage of oxidative stress, YY1 exhibited less affinity toward the Cxcl12 promoter while PARP-1 displayed strong binding. These interactions were accompanied by Cxcl12 downregulation. In the later stages of oxidative stress and intensive pancreatic beta cell injury, YY1 was highly expressed and firmly bound to Cxcl12 promoter in contrast to PARP-1. These interactions resulted in higher Cxcl12 expression. The observed ability of PARP-1 to downregulate, and of YY1 to upregulate Cxcl12 promoter activity anticipates corresponding effects in the natural context where the functional interplay of these proteins could finely balance Cxcl12 transcription.
authors.affiliation: Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia.
authors.forename: Jelena
authors.initials: J
authors.lastname: Marković
authors.forename: Nevena
authors.initials: N
authors.lastname: Grdović
authors.forename: Svetlana
authors.initials: S
authors.lastname: Dinić
authors.forename: Teodora
authors.initials: T
authors.lastname: Karan-Djurašević
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Uskoković
authors.forename: Jelena
authors.initials: J
authors.lastname: Arambašić
authors.forename: Mirjana
authors.initials: M
authors.lastname: Mihailović
authors.forename: Sonja
authors.initials: S
authors.lastname: Pavlović
authors.forename: Goran
authors.initials: G
authors.lastname: Poznanović
authors.forename: Melita
authors.initials: M
authors.lastname: Vidaković
mesh_terms: D000818:Animals; D001481:Basal Metabolism / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D054377:Chemokine CXCL12 / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D051381:Rats; D013311:Streptozocin / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D050986:YY1 Transcription Factor / Q000378:metabolism*
chemical_list: D054377:Chemokine CXCL12; D050986:YY1 Transcription Factor; C494700:Yy1 protein, rat; D013311:Streptozocin; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
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