title: Epigenetic control of hypoxia inducible factor-1α-dependent expression of placental growth factor in hypoxic conditions.
abstract: Hypoxia plays a crucial role in the angiogenic switch, modulating a large set of genes mainly through the activation of hypoxia-inducible factor (HIF) transcriptional complex. Endothelial cells play a central role in new vessels formation and express placental growth factor (PlGF), a member of vascular endothelial growth factor (VEGF) family, mainly involved in pathological angiogenesis. Despite several observations suggest a hypoxia-mediated positive modulation of PlGF, the molecular mechanism governing this regulation has not been fully elucidated. We decided to investigate if epigenetic modifications are involved in hypoxia-induced PlGF expression. We report that PlGF expression was induced in cultured human and mouse endothelial cells exposed to hypoxia (1% O 2), although DNA methylation at the Plgf CpG-island remains unchanged. Remarkably, robust hyperacetylation of histones H3 and H4 was observed in the second intron of Plgf, where hypoxia responsive elements (HREs), never described before, are located. HIF-1α, but not HIF-2α, binds to identified HREs. Noteworthy, only HIF-1α silencing fully inhibited PlGF upregulation. These results formally demonstrate a direct involvement of HIF-1α in the upregulation of PlGF expression in hypoxia through chromatin remodeling of HREs sites. Therefore, PlGF may be considered one of the putative targets of anti-HIF therapeutic applications.
authors: Istituto di Genetica e Biofisica "Adriano Buzzati-Traverso"; National Research Council; Napoli, Italy.
authors: Laura
authors: L
authors: Tudisco
authors: Istituto di Genetica e Biofisica "Adriano Buzzati-Traverso"; National Research Council; Napoli, Italy; Istituto di Ricovero e Cura a Carattere Scientifico Neuromed; Pozzilli, Italy.
authors: Floriana
authors: F
authors: Della Ragione
authors: Istituto di Genetica e Biofisica "Adriano Buzzati-Traverso"; National Research Council; Napoli, Italy.
authors: Valeria
authors: V
authors: Tarallo
authors: Istituto di Genetica e Biofisica "Adriano Buzzati-Traverso"; National Research Council; Napoli, Italy.
authors: Ivana
authors: I
authors: Apicella
authors: Istituto di Genetica e Biofisica "Adriano Buzzati-Traverso"; National Research Council; Napoli, Italy; Istituto di Ricovero e Cura a Carattere Scientifico Neuromed; Pozzilli, Italy.
authors: Maurizio
authors: M
authors: D'Esposito
authors: Istituto di Genetica e Biofisica "Adriano Buzzati-Traverso"; National Research Council; Napoli, Italy; Istituto di Ricovero e Cura a Carattere Scientifico Neuromed; Pozzilli, Italy.
authors: Maria Rosaria
authors: MR
authors: Matarazzo
authors: Istituto di Genetica e Biofisica "Adriano Buzzati-Traverso"; National Research Council; Napoli, Italy.
authors: Sandro
authors: S
authors: De Falco
mesh_terms: D000107:Acetylation; D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D018899:CpG Islands; D019175:DNA Methylation; D042783:Endothelial Cells / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D055806:Microvessels / Q000166:cytology; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic
chemical_list: D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor
keywords: DNA methylation; VEGF family; angiogenesis; chromatin; histone modification; hypoxia; hypoxia inducible factor (HIF); placental growth factor (PlGF)