HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA-forming microsatellite
HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA-forming microsatellite
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DOI：
10.1182/blood-2006-12-063289
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发表时间：
2007-10-15
期刊：
影响因子：
20.3
通讯作者：
Srai, Surjit Kaila S.
中科院分区：
文献类型：
--
作者：
Bayele, Henry K.;Peyssonnaux, Carole;Srai, Surjit Kaila S.
ITY/LSH/BCG基因座编码巨噬细胞蛋白Slc11a1/Nramp1，可保护近交系小鼠免受各种细胞内病原体的感染，包括利什曼原虫、分枝杆菌和沙门氏菌。人类对感染和炎症性疾病的易感性，包括类风湿性关节炎、炎症性肠病和结核病，显示出与SLC11A1近端启动子内高度多态的调节性Z-DNA形成微卫星(GT/AC)(N)二核苷酸的等位基因相关。我们推测顺式作用的等位基因多态可能是SLC11A1表达的遗传差异和疾病风险的表型差异的基础。然而，目前尚不清楚SLC11A1等位基因表达的这种差异背后的原因。在这里，我们表明，缺氧诱导因子1(HIF-1)通过在感染或炎症激活巨噬细胞过程中直接与微卫星结合来调节SLC11A1表达的等位基因变化。靶向HIF-1α消融小鼠巨噬细胞可降低SLc11a11的表达和对S鼠伤寒杆菌感染的反应性。我们的数据还表明，HIF-1可能在功能上与某些SLC11A1等位基因相关的复杂典型炎症性疾病有关。由于这些等位基因高度多态，我们的发现表明，HIF-1可能影响SLC11A1依赖的先天感染和炎症抵抗力在群体内和群体之间的可遗传变异。这份报告还表明，微卫星可能通过调节基因表达表型，在复杂可遗传性状的定向进化中发挥关键作用。
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.