Transcription factor ATF-3 regulates allele variation phenotypes of the human SLC11A1 gene

• DOI: 10.1007/s11033-012-2289-1
• Publication Date: 2012-11-26T19:51:05Z
• Authors: Styliani Taka; Maria Gazouli; Panagotis K. Politis; Kalliopi I. Pappa; Nicholas P. Anagnou
• Keywords: 0301 basic medicine; 570; 0303 health sciences; Activating Transcription Factor 3; Polymorphism, Genetic; Proto-Oncogene Proteins c-jun; Genetic Variation; Cell Line; 3. Good health; 03 medical and health sciences; Phenotype; Gene Expression Regulation; Humans; Promoter Regions, Genetic; Cation Transport Proteins; Alleles; Microsatellite Repeats; Protein Binding

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.