Tiana, M., Villar, D., Pérez-Guijarro, E., Gómez-Maldonado, L., Moltó, E., Fernández-Miñán, A., Gómez-Skarmeta, J.L., Montoliu, L., and Del Peso, L. (2012) A role for insulator elements in the regulation of gene expression response to hypoxia. Nucleic acids research. 40(5):1916-1927.
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