title: A role for insulator elements in the regulation of gene expression response to hypoxia.
abstract: Hypoxia inducible factor (HIF) up-regulates the transcription of a few hundred genes required for the adaptation to hypoxia. This restricted set of targets is in sharp contrast with the widespread distribution of the HIF binding motif throughout the genome. Here, we investigated the transcriptional response of GYS1 and RUVBL2 genes to hypoxia to understand the mechanisms that restrict HIF activity toward specific genes. GYS1 and RUVBL2 genes are encoded by opposite DNA strands and separated by a short intergenic region (~1 kb) that contains a functional hypoxia response element equidistant to both genes. However, hypoxia induced the expression of GYS1 gene only. Analysis of the transcriptional response of chimeric constructs derived from the intergenic region revealed an inhibitory sequence whose deletion allowed RUVBL2 induction by HIF. Enhancer blocking assays, performed in cell culture and transgenic zebrafish, confirmed the existence of an insulator element within this inhibitory region that could explain the differential regulation of GYS1 and RUVBL2 by hypoxia. Hence, in this model, the selective response to HIF is achieved with the aid of insulator elements. This is the first report suggesting a role for insulators in the regulation of differential gene expression in response to environmental signals.
authors: Departamento de Bioquímica, Universidad Autónoma de Madrid and Instituto de Investigaciones Biomedicas Alberto Sols, CSIC-UAM, 28029 Madrid, Spain.
authors: Maria
authors: M
authors: Tiana
authors: Diego
authors: D
authors: Villar
authors: Eva
authors: E
authors: Pérez-Guijarro
authors: Laura
authors: L
authors: Gómez-Maldonado
authors: Eduardo
authors: E
authors: Moltó
authors: Ana
authors: A
authors: Fernández-Miñán
authors: Jose Luis
authors: JL
authors: Gómez-Skarmeta
authors: Lluís
authors: L
authors: Montoliu
authors: Luis
authors: L
authors: del Peso
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D015687:Cell Hypoxia; D002460:Cell Line; D004265:DNA Helicases / Q000096:biosynthesis / Q000235:genetics; D021901:DNA, Intergenic / Q000737:chemistry; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006006:Glycogen Synthase / Q000235:genetics; D006801:Humans; D038101:Insulator Elements
chemical_list: D002352:Carrier Proteins; D021901:DNA, Intergenic; D006006:Glycogen Synthase; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; C122079:RUVBL2 protein, human