title: Epigenetic regulation of the formyl peptide receptor 2 gene.
abstract: Lipoxin (LX) A4, a main stop signal of inflammation, exerts potent bioactions by activating a specific G protein-coupled receptor, termed formyl peptide receptor 2 and recently renamed ALX/FPR2. Knowledge of the regulatory mechanisms that drive ALX/FPR2 gene expression is key for the development of innovative anti-inflammatory pharmacology. Here, we examined chromatin patterns of the ALX/FPR2 gene. We report that in MDA-MB231 breast cancer cells, the ALX/FPR2 gene undergoes epigenetic silencing characterized by low acetylation at lysine 27 and trimethylation at lysine 4, associated with high methylation at lysine 27 of histone 3. This pattern, which is consistent with transcriptionally inaccessible chromatin leading to low ALX/FPR2 mRNA and protein expression, is reversed in polymorphonuclear leukocytes that express high ALX/FPR2 levels. Activation of p300 histone acetyltransferase and inhibition of DNA methyltransferase restored chromatin accessibility and significantly increased ALX/FPR2 mRNA transcription and protein levels in MDA-MB231 cells, as well as in pulmonary artery endothelial cells. In both cells types, changes in the histone acetylation/methylation status enhanced ALX/FPR2 signaling in response to LXA4. Collectively, these results uncover unappreciated epigenetic regulation of ALX/FPR2 expression that can be exploited for innovative approaches to inflammatory disorders.
authors.affiliation: Department of Medical, Oral, and Biotechnological Science, "G. D'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11/13, 66100 Chieti, Italy; Center of Aging Sciences and Translational Medicine (CeSI-MeT), "G. D'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11/13, 66100 Chieti, Italy.
authors.forename: Felice
authors.initials: F
authors.lastname: Simiele
authors.affiliation: Department of Medical, Oral, and Biotechnological Science, "G. D'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11/13, 66100 Chieti, Italy; Center of Aging Sciences and Translational Medicine (CeSI-MeT), "G. D'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11/13, 66100 Chieti, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Recchiuti
authors.affiliation: Department of Medical, Oral, and Biotechnological Science, "G. D'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11/13, 66100 Chieti, Italy; Center of Aging Sciences and Translational Medicine (CeSI-MeT), "G. D'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11/13, 66100 Chieti, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Patruno
authors.affiliation: Department of Medical, Oral, and Biotechnological Science, "G. D'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11/13, 66100 Chieti, Italy; Center of Aging Sciences and Translational Medicine (CeSI-MeT), "G. D'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11/13, 66100 Chieti, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Plebani
authors.affiliation: Department of Medicine and Aging Science, "G. D'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11/13, 66100 Chieti, Italy; Center of Aging Sciences and Translational Medicine (CeSI-MeT), "G. D'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11/13, 66100 Chieti, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Pierdomenico
authors.affiliation: Department of Medical, Oral, and Biotechnological Science, "G. D'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11/13, 66100 Chieti, Italy; Center of Aging Sciences and Translational Medicine (CeSI-MeT), "G. D'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11/13, 66100 Chieti, Italy.
authors.forename: Marilina
authors.initials: M
authors.lastname: Codagnone
authors.affiliation: Department of Medical, Oral, and Biotechnological Science, "G. D'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11/13, 66100 Chieti, Italy; Center of Aging Sciences and Translational Medicine (CeSI-MeT), "G. D'Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11/13, 66100 Chieti, Italy. Electronic address: mromano@unich.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Romano
mesh_terms: D000107:Acetylation; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D044045:Lipoxins / Q000378:metabolism* / Q000494:pharmacology; D008745:Methylation; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000235:genetics* / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002843:Chromatin; C105101:FPR2 protein, human; D006657:Histones; D044045:Lipoxins; D012333:RNA, Messenger; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C040527:lipoxin A4; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human
keywords: Chromatin; G protein-coupled receptors; Histones; Inflammation; Lipoxins