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Blood, 15 October 2007, Vol. 110, No. 8, pp. 3039-3048. Prepublished online as a Blood First Edition Paper on July 2, 2007; DOI 10.1182/blood-2006-12-063289.
PHAGOCYTES HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA–forming microsatellite1 Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom; 2 Division of Biological Sciences, 3 Department of Pediatrics, University of California, San Diego, La Jolla, CA; 4 Departments of Pathology and Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis, Greece; 5 Department of Parasitology, Institute of Biology, Universidade Estadual de Campinas, São Paolo, Brazil; 6 Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom; and 7 Department of Infectious Diseases, King's College London, London, United Kingdom
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
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
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. 
