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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.
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Submitted December 21, 2006
Accepted June 13, 2007
HIF-1 regulates heritable variation and allele
expression phenotypes of the macrophage immune response
gene SLC11A1 from a Z-DNA-forming microsatellite
Henry K Bayele*, Carole Peyssonnaux, Alexandra Giatromanolaki, Wagner W Arrais-Silva, Hiba S Mohamed, Helen Collins, Selma Giorgio, Michael Koukourakis, Randall S Johnson, Jenefer M Blackwell, Victor Nizet, and Surjit Kaila S. Srai
Department of Biochemistry & Molecular Biology, University College London, London, United Kingdom
Division of Biological Sciences, University of California, San Diego, La Jolla, CA, United States
Departments of Pathology and Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis, Greece
Department of Parasitology, Institute of Biology, Universidade Estadual de Campinas, Campinas, Brazil
Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
GKT School of Biomedical Sciences, King's College London, Guy's Campus, London, United Kingdom
Department of Pediatrics, University of California, San Diego, La Jolla, CA, United States
* Corresponding author; email: h.bayele{at}medsch.ucl.ac.uk.
The Ity/Lsh/Bcg locus encodes the macrophage protein Slc11a1 (formerly Nramp1) and protects inbred mice against infection by diverse intracellular pathogens including Leishmania, Mycobacterium and Salmonella. In humans, susceptibility to infectious and inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease and tuberculosis, shows allelic association with a highly polymorphic regulatory microsatellite of (GT/AC)n dinucleotides within the SLC11A1 promoter. However it is unclear what determines SLC11A1 allele expression phenotypes. We surmised that cis-acting allelic polymorphisms may underlie heritable differences in SLC11A1 expression which could contribute to phenotypic variation in disease risk. Here we show that Hypoxia-Inducible Factor 1 (HIF-1), a transcription factor commonly associated with oxygen homeostasis, energy metabolism and tumorigenesis, regulates SLC11A1 allele expression phenotypes by binding directly to the microsatellite during macrophage activation by pathogen and pro-inflammatory stimuli. We show that the microsatellite has Z-DNA-forming propensity both in vitro and in vivo. Targeted HIF-1 ablation in murine macrophages attenuated Slc11a11 expression in response to S. typhimurium infection. Our data also suggest that HIF-1 may be functionally linked to complex prototypical human diseases associated with SLC11A1 alleles. As these alleles are highly polymorphic and are distributed according to race and ethnicity, our finding suggests that HIF-1 may act in trans to influence heritable variation in SLC11A1-dependent innate resistance to infection and inflammation within and between populations, thus redefining HIF-1 as a potential regulator of innate immunity. This report also suggests that microsatellites may play critical roles in the directional evolution of complex heritable traits by regulating gene expression phenotypes.
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