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Transcriptional regulation of the human FPR2/ALX gene: evidence of a heritable genetic variant that impairs promoter activity
Author(s) -
Simiele Felice,
Recchiuti Antonio,
Mattoscio Domenico,
De Luca Antonella,
Cianci Eleonora,
Franchi Sara,
Gatta Valentina,
Parolari Alessandro,
Werba Jose Pablo,
Camera Marina,
Favaloro Bartolo,
Romano Mario
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-198069
Subject(s) - gene , genetics , biology , promoter , transcriptional regulation , transcription factor , gene expression
Lipoxin (LX) A4 a main endogenous stop‐signal 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 immuno‐precipitation 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 MDA‐MB231 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 —Simiele, F., Recchiuti, A., Mattoscio, D., De Luca, A., Cianci, E., Franchi, S., Gatta, V., Parolari, A., Werba, J. P., Camera, M., Favaloro, B., Romano, M. Transcriptional regulation of the human FPR2/ALX gene: Evidence of a heritable genetic variant that impairs promoter activity. FASEB J. 26, 1323‐1333 (2012). www.fasebj.org