4.5 Article

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

Journal

MOLECULAR BIOLOGY REPORTS
Volume 40, Issue 3, Pages 2263-2271

Publisher

SPRINGER
DOI: 10.1007/s11033-012-2289-1

Keywords

SLC11A1; ATF-3; c-Jun; Transcriptional regulation; Innate resistance

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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)(5)AC(GT)(5)AC(GT)(10)GGCAGA(G)(6)], and Allele 3, [T(GT)(5)AC(GT)(5)AC(GT)(9)GGCAGA(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.

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