HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA forming microsatellite.
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-1alpha 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.
Bayele
Henry K
HK
Department of Biochemistry & Molecular Biology, University College London, NW3 2PF, United Kingdom. h.bayele@medsch.ucl.ac.uk
Peyssonnaux
Carole
C
Giatromanolaki
Alexandra
A
Arrais-Silva
Wagner W
WW
Mohamed
Hiba S
HS
Collins
Helen
H
Giorgio
Selma
S
Koukourakis
Michael
M
Johnson
Randall S
RS
Blackwell
Jenefer M
JM
Nizet
Victor
V
Srai
Surjit Kaila S
SK
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000235:genetics*; D043542:DNA, Z-Form / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007150:Immunohistochemistry; D008262:Macrophage Activation / Q000235:genetics*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018895:Microsatellite Repeats / Q000235:genetics*; D008969:Molecular Sequence Data; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012480:Salmonella Infections / Q000276:immunology; D014158:Transcription, Genetic; D014162:Transfection; D000099173:Natural Resistance-associated Macrophage Protein 1
D027682:Cation Transport Proteins; D043542:DNA, Z-Form; D051793:Hypoxia-Inducible Factor 1; D000099173:Natural Resistance-associated Macrophage Protein 1