The 5’ promoter region of the Human Solute Carrier family 11 member 1 protein (SLC11A1): linking Infections, Autoimmunity and Cancer?
Slc11a1 in mouse encodes an integral membrane protein, expressed in myeloid lineage in the endosomal/lysosomal compartment and localized to vesicles in neurons. Slc11a1 is a Ph-dependent proton/divalent cation antiporter involved in macrophage function. The SLC11A1 gene, located on human chromosome 2q35, is ~14kb in length and contains 15 exons. Analysis of linkage disequilibrium (LD) of SNPs across the 14 kb SLC11A1 gene showed two distinct patterns of tight LD in The Gambian and Chinese populations: there is high LD among markers in the 5’ region and among markers in the 3’ region, but not between these markers. We have carried out LD studies in 8 global populations and confirmed this finding by demonstrating linkage equilibrium (LE) between 8 microsatellite markers encompassing 3 cM of this gene. Interestingly, most published SCL11A1 associations with infections, (ranging from viral to protozoan), autoimmunity, multiple sclerosis and cancer in different human populations are with a 5’ Z-DNA forming promoter region microsatellite polymorphism. Comparative genomics of the SLC11A1 region in mouse and human reveals a protein with highly conserved amino acid sequence across species but striking nucleotide differences at the 5’ & 3’ untranslated regions (UTRs) and within intronic regions. One difference is the Activating Transcription Factor-3 binding site (ATF-3; also known as AP-1 like element) just immediate to the 5’ of this Z-DNA forming microsatellite polymorphism in humans but not in mouse. We hypothesis that when the homodimer ATF-3 binds to this target sequence in the 5’ promoter region of SLC11A1, it should repress transcriptional activation of SLC11A1, in accordance with the notion that genes that deplete the iron content of the cell cytosol antagonize cell growth. We have identified polymorphisms at this ATF-3 putative binding site in several human populations. We are investigating the role of the ATF-3 in mediating the activation/repression of SLC11A1. This study should aid in understanding the underlying mechanism by which a balance is maintained between infections caused by intracellular pathogens and disorders resulting from chronic inflammation. Results obtained thus far will be presented.