Inducible nitric oxide synthase (iNOS) regulatory region variation in non-human primates

Abstract

Inducible nitric oxide synthase (iNOS) is an enzyme that plays a key role in intracellular immune response against respiratory infections. Since various species of nonhuman primates exhibit different levels of susceptibility to infectious respiratory diseases, and since variation in regulatory regions of genes is thought to play a key role in expression levels of genes, two candidate regulatory regions of iNOS were mapped, sequenced, and compared across five species of nonhuman primates: African green monkeys (chlorocebus sabeus), pig-tailed macaques (Macaca mulatta), cynomolgus macaques (Macaca fascicularis), Indian rhesus macaques (Macaca mulatta), and Chinese rhesus macaques (M. mulatta). In addition, we conducted an in silico analysis of the transcription factor binding sites associated with genetic variation in these two candidate regulatory regions across species. We found that only one of the two candidate regions showed strong evidence of involvement in iNOS regulation. Specifically, we found evidence of 13 conserved binding site candidates linked to iNOS regulation: AP-1, C/EBPB, CREB, GATA-1, GATA-3, NF-AT, NF-AT5, NF-κB, KLF4, Oct-1, PEA3, SMAD3, and TCF11. Additionally, we found evidence of interspecies variation in binding sites for several regulatory elements linked to iNOS (GATA-3, GATA-4, KLF6, SRF, STAT-1, STAT-3, OLF-1 and HIF-1) across species, especially in African green monkeys relative to other species. Given the key role of iNOS in respiratory immune response, the findings of this study might help guide the direction of future studies aimed to uncover the molecular mechanisms underlying the increased susceptibility of African green monkeys to several viral and bacterial respiratory infections.

The PPE2 protein of Mycobacterium tuberculosis translocates to host nucleus and inhibits nitric oxide production

“…In addition to major role played by NF-κB and IRF-121, binding sites of several other transcription factors linked to iNOS regulation are found to be conserved that include GATA-122. Using Alibaba2.1 (http://wwwiti.cs.uni-magdeburg.de/-grabe/alibaba2)23, we found at least five putative GATA-1 binding sites in the 5′-upstream region of the transcriptional start site.…”

Transcriptomic Profiles of Monocyte-Derived Macrophages in Response to Escherichia coli is Associated with the Host Genetics

“…Although it should be noted that FDR p-value of IRF8 and SPI1 was not significant in our study, their unadjusted p-values were less than 0.05. In five species of non-human primates, a conserved regulatory binding site for STAT1, HIF-1, NFAT5 that controls the expression of iNOS has been previously reported 40 . In addition, interactions between HIF-1 and IRF-1, and HIF-1 and STAT1 have also been reported in mice, and these regulate the expression of iNOS and induce apoptosis in cancer cells 40,41 .…”

“…In five species of non-human primates, a conserved regulatory binding site for STAT1, HIF-1, NFAT5 that controls the expression of iNOS has been previously reported 40 . In addition, interactions between HIF-1 and IRF-1, and HIF-1 and STAT1 have also been reported in mice, and these regulate the expression of iNOS and induce apoptosis in cancer cells 40,41 . Although, this information supports the association between NO-based phenotypes and these TFs (summarized in Fig.…”

Nutraceuticals Targeting Generation and Oxidant Activity of Peroxynitrite May Aid Prevention and Control of Parkinson’s Disease

“…The induction of iNOS is a feature of microglial activation and involves joint activation of NF-kappaB and AP-1 transcription factors, each of which bind to the iNOS promoter [65][66][67][68][69][70][71][72]. The sustained microglial activation in PD appears likely to reflect DAMP-mediated activation of certain toll-like receptors (notably TLR2 and TLR4), as well as the receptor of advanced glycation end-products (RAGE) and the integrin receptor Mac1 [73][74][75][76].…”