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

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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.

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Authors and Affiliations

  1. Laboratory of Biology, University of Athens School of Medicine, 176 Michalakopoulou Street, 115 27, Athens, Greece

    Styliani Taka, Maria Gazouli & Nicholas P. Anagnou

  2. Histology Laboratory, Centre of Basic Research I, Biomedical Research Foundation, Academy of Athens (BRFAA), 4 Soranou Ephessiou Street, 115 27, Athens, Greece

    Panagotis K. Politis

  3. Cell and Gene Therapy Laboratory, Centre of Basic Research, Biomedical Research Foundation, Academy of Athens (BRFAA), 4 Soranou Ephessiou Street, 115 27, Athens, Greece

    Kalliopi I. Pappa & Nicholas P. Anagnou

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  1. Styliani Taka
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Taka, S., Gazouli, M., Politis, P.K. et al. Transcription factor ATF-3 regulates allele variation phenotypes of the human SLC11A1 gene. Mol Biol Rep 40, 2263–2271 (2013). https://doi.org/10.1007/s11033-012-2289-1

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