HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA forming microsatellite Export

@article{citeulike:1688718, abstract = {The Ity/Lsh/Bcg locus encodes the macrophage protein Slc11a1/Nramp1, which protects inbred mice against infection by diverse intracellular pathogens including Leishmania, Mycobacterium, and Salmonella. Human susceptibility to infectious and inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and tuberculosis, shows allelic association with a highly polymorphic regulatory, Z-DNA-forming microsatellite of (GT/AC)n dinucleotides within the proximal SLC11A1 promoter. We surmised that cis-acting allelic polymorphisms may underlie heritable differences in SLC11A1 expression and phenotypic variation in disease risk. However, it is unclear what may underlie such variation in SLC11A1 allele expression. Here we show that hypoxia-inducible Factor 1 (HIF-1) regulates allelic variation in SLC11A1 expression by binding directly to the microsatellite during macrophage activation by infection or inflammation. Targeted Hif-1{alpha} ablation in murine macrophages attenuated Slc11a11 expression and responsiveness to S typhimurium infection. Our data also showed that HIF-1 may be functionally linked to complex prototypical inflammatory diseases associated with certain SLC11A1 alleles. As these alleles are highly polymorphic, our finding suggests that HIF-1 may influence heritable variation in SLC11A1-dependent innate resistance to infection and inflammation within and between populations. This report also suggests that microsatellites may play critical roles in the directional evolution of complex heritable traits by regulating gene expression phenotypes. 10.1182/blood-2006-12-063289}, author = {Bayele, Henry K. and Peyssonnaux, Carole and Giatromanolaki, Alexandra and Arrais-Silva, Wagner W. and Mohamed, Hiba S. and Collins, Helen and Giorgio, Selma and Koukourakis, Michael and Johnson, Randall S. and Blackwell, Jenefer M. and Nizet, Victor and Srai, Surjit K.}, citeulike-article-id = {1688718}, citeulike-linkout-0 = {http://dx.doi.org/10.1182/blood-2006-12-063289}, citeulike-linkout-1 = {http://bloodjournal.hematologylibrary.org/content/110/8/3039.abstract}, citeulike-linkout-2 = {http://bloodjournal.hematologylibrary.org/content/110/8/3039.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/17606764}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=17606764}, day = {15}, doi = {10.1182/blood-2006-12-063289}, journal = {Blood}, keywords = {z-dna}, month = {October}, number = {8}, pages = {3039--3048}, posted-at = {2009-11-09 07:57:48}, priority = {2}, title = {HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA forming microsatellite}, url = {http://dx.doi.org/10.1182/blood-2006-12-063289}, volume = {110}, year = {2007} }

TY - JOUR ID - citeulike:1688718 L3 - citeulike-article-id:1688718 N2 - The Ity/Lsh/Bcg locus encodes the macrophage protein Slc11a1/Nramp1, which protects inbred mice against infection by diverse intracellular pathogens including Leishmania, Mycobacterium, and Salmonella. Human susceptibility to infectious and inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and tuberculosis, shows allelic association with a highly polymorphic regulatory, Z-DNA-forming microsatellite of (GT/AC)n dinucleotides within the proximal SLC11A1 promoter. We surmised that cis-acting allelic polymorphisms may underlie heritable differences in SLC11A1 expression and phenotypic variation in disease risk. However, it is unclear what may underlie such variation in SLC11A1 allele expression. Here we show that hypoxia-inducible Factor 1 (HIF-1) regulates allelic variation in SLC11A1 expression by binding directly to the microsatellite during macrophage activation by infection or inflammation. Targeted Hif-1{alpha} ablation in murine macrophages attenuated Slc11a11 expression and responsiveness to S typhimurium infection. Our data also showed that HIF-1 may be functionally linked to complex prototypical inflammatory diseases associated with certain SLC11A1 alleles. As these alleles are highly polymorphic, our finding suggests that HIF-1 may influence heritable variation in SLC11A1-dependent innate resistance to infection and inflammation within and between populations. This report also suggests that microsatellites may play critical roles in the directional evolution of complex heritable traits by regulating gene expression phenotypes. 10.1182/blood-2006-12-063289 IS - 8 JF - Blood EP - 3048 TI - HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA forming microsatellite VL - 110 SP - 3039 KW - z-dna AU - Bayele, Henry AU - Peyssonnaux, Carole AU - Giatromanolaki, Alexandra AU - Arrais-Silva, Wagner AU - Mohamed, Hiba AU - Collins, Helen AU - Giorgio, Selma AU - Koukourakis, Michael AU - Johnson, Randall AU - Blackwell, Jenefer AU - Nizet, Victor AU - Srai, Surjit PY - 2007/10/15/ UR - http://dx.doi.org/10.1182/blood-2006-12-063289 ER -