Transcriptional regulation of the human FPR2/ALX gene: Evidence of a heritable genetic variant that impairs promoter activity

Felice Simiele, Antonio Recchiuti, Domenico Mattoscio, Antonella De Luca, Eleonora Cianci, Sara Franchi, Valentina Gatta, Alessandro Parolari, Josè Pablo Werba, Marina Camera, Bartolo Favaloro, Mario Romano

Research output: Contribution to journalArticlepeer-review

Abstract

Lipoxin (LX) A 4, a main endogenous stopsignal of inflammation, activates the G-protein-coupled receptor FPR2/ALX, which triggers potent anti-inflammatory signaling in vivo. Thus, the regulation of FPR2/ALX expression may have pathophysiological and therapeutic relevance. Here, we mapped a nucleotide sequence with strong FPR2/ALX promoter activity. Chromatin immunoprecipitation revealed specificity protein 1 (Sp1) binding to the core promoter. Site-directed mutagenesis of the Sp1 cis-acting element and Sp1 overexpression established that this transcription factor is key for maximal promoter activity, which is instead suppressed by DNA methylation. LXA 4 enhanced FPR2/ALX promoter activity (+74%) and mRNA expression (+87.5%) in MDAMB231 cells. A single nucleotide mutation (A/G) was detected in the core promoter of one subject with history of cardiovascular disease and of his two daughters. This mutation reduced by ∼35-90% the promoter activity in vitro. Moreover, neutrophils from individuals carrying the A/G variant displayed ∼10- and 3-fold reduction in FPR2/ALX mRNA and protein, respectively, compared with cells from their relatives or healthy volunteers expressing the wild-type allele. These results uncover FPR2/ ALX transcriptional regulation and provide the first evidence of mutations that affect FPR2/ALX transcription, thus opening new opportunities for the understanding of the LXA 4-FPR2/ALX axis in human disease.

Original languageEnglish
Pages (from-to)1323-1333
Number of pages11
JournalFASEB Journal
Volume26
Issue number3
DOIs
Publication statusPublished - Mar 2012

Keywords

  • Inflammation
  • Lipoxin A receptor
  • Methylation
  • Polymorphism
  • Sp1

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

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