title: Transcription factor ATF-3 regulates allele variation phenotypes of the human SLC11A1 gene.
abstract: Genetic polymorphisms in the human solute carrier family 11 member 1 (SLC11A1) gene predispose to susceptibility to infectious/inflammatory diseases and cancer. Human susceptibility to these diseases exhibits allelic association with a polymorphic regulatory Z-DNA-forming microsatellite of a (GT/AC)n repeat. The carriage of different alleles may influence chromatin remodeling and accessibility by transcription factors. Of particular importance is the binding site for the Activating Protein 1 (AP-1) elements, (ATF-3 and c-Jun), adjacent to the 5' sequence of the Z-DNA-forming polymorphism. The aim of the study was to characterize the transcriptional mechanisms controlling different alleles of SLC11A1 expression by ATF-3 and c-Jun. Allele 2, [T(GT)5AC(GT)5AC(GT)10GGCAGA(G)6], and Allele 3, [T(GT)5AC(GT)5AC(GT)9GGCAGA(G)6], were subcloned into the PGL2Basic vector. Transient transfections of THP-1 cells with the constructs, in the presence or absence of pATF-3 were preformed. Luciferase expression was determined. To document the recruitment of ATF-3 and c-Jun, to the polymorphic promoter alleles in vivo, we performed ChIP assays with transient transfected THP-1 cells treated with or without lipopolyssacharides. Our data documented that ATF-3 suppresses the transcriptional activation of Allele-3, and this suppression is enhanced in the presence of lipopolyssacharides. Our findings suggest that ATF-3 and c-Jun may influence heritable variation in SLC11A1-dependent innate resistance to infection and inflammation both within and between populations.
authors.affiliation: Laboratory of Biology, University of Athens School of Medicine, 176 Michalakopoulou Street, 115 27, Athens, Greece.
authors.forename: Styliani
authors.initials: S
authors.lastname: Taka
authors.forename: Maria
authors.initials: M
authors.lastname: Gazouli
authors.forename: Panagotis K
authors.initials: PK
authors.lastname: Politis
authors.forename: Kalliopi I
authors.initials: KI
authors.lastname: Pappa
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Anagnou
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D000483:Alleles; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D018895:Microsatellite Repeats; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D000099173:Natural Resistance-associated Macrophage Protein 1
chemical_list: D051700:Activating Transcription Factor 3; D027682:Cation Transport Proteins; D016755:Proto-Oncogene Proteins c-jun; D000099173:Natural Resistance-associated Macrophage Protein 1