Regulation of human formyl peptide receptor 1 synthesis: role of single nucleotide polymorphisms, transcription factors, and inflammatory mediators

dc.contributor.authorMiettinen, Heini M.
dc.description.abstractThe gene encoding the human formyl peptide receptor 1 (FPR1) is heterogeneous, containing numerous single nucleotide polymorphisms (SNPs). Here, we examine the effect of these SNPs on gene transcription and protein translation. We also identify gene promoter sequences and putative FPR1 transcription factors. To test the effect of codon bias and codon pair bias on FPR1 expression, four FPR1 genetic variants were expressed in human myeloid U937 cells fused to a reporter gene encoding firefly luciferase. No significant differences in luciferase activity were detected, suggesting that the translational regulation and protein stability of FPR1 are modulated by factors other than the SNP codon bias and the variant amino acid properties. Deletion and mutagenesis analysis of the FPR1 promoter showed that a CCAAT box is not required for gene transcription. A −88/41 promoter construct resulted in the strongest transcriptional activity, whereas a −72/41 construct showed large reduction in activity. The region between −88 and −72 contains a consensus binding site for the transcription factor PU.1. Mutagenesis of this site caused significant reduction in reporter gene expression. The PU.1 binding was confirmed in vivo by chromatin immunoprecipitation, and the binding to nucleotides −84 to −76 (TTCCTATTT) was confirmed in vitro by an electrophoretic mobility shift assay. Thus, similar to many other myeloid genes, FPR1 promoter activity requires PU.1. Two single nucleotide polymorphisms at −56 and −54 did not significantly affect FPR1 gene expression, despite differences in binding of transcription factor IRF1 in vitro. Inflammatory mediators such as interferon-γ, tumor necrosis factor-α, and lipopolysaccharide did not increase FPR1 promoter activity in myeloid cells, whereas differentiation induced by DMSO and retinoic acid enhanced the activity. This implies that the expression of FPR1 in myeloid cells is developmentally regulated, and that the differentiated cells are equipped for immediate response to microbial infections.en_US
dc.description.sponsorshipNational Institutes of Health National Institute of Allergy and Infectious Diseases grant 1R21 AI83244-02; NIH National Center for Research Resources INBRE award P20 RR016455en_US
dc.identifier.citationMiettinen, Heini M. “Regulation of Human Formyl Peptide Receptor 1 Synthesis: Role of Single Nucleotide Polymorphisms, Transcription Factors, and Inflammatory Mediators.” Edited by Samithamby Jeyaseelan. PLoS ONE 6, no. 12 (December 9, 2011): e28712. doi:10.1371/journal.pone.0028712.en_US
dc.rightsCC BY: This license lets you distribute, remix, tweak, and build upon this work, even commercially, as long as you credit the original creator for this work. This is the most accommodating of licenses offered. Recommended for maximum dissemination and use of licensed materials.en_US
dc.titleRegulation of human formyl peptide receptor 1 synthesis: role of single nucleotide polymorphisms, transcription factors, and inflammatory mediatorsen_US
mus.citation.journaltitlePLoS Oneen_US
mus.contributor.orcidMiettinen, Heini M.|0000-0001-6249-8615en_US
mus.identifier.categoryHealth & Medical Sciencesen_US
mus.relation.collegeCollege of Letters & Scienceen_US
mus.relation.departmentMicrobiology & Immunology.en_US
mus.relation.researchgroupMT INBRE Bioinformatics and Biostatistics Core.en_US
mus.relation.universityMontana State University - Bozemanen_US


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