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Title

Cooperativity of stress-responsive transcription factors in core hypoxia-inducible factor binding regions

AuthorsVillar, Diego; Ortiz-Barahona, Amaya; Gómez-Maldonado, Laura; Pescador, Nuria; Peso, Luis del
Issue Date24-Sep-2012
PublisherPublic Library of Science
CitationPLoS ONE 7(9): e45708 (2012)
AbstractThe transcriptional response driven by Hypoxia-inducible factor (HIF) is central to the adaptation to oxygen restriction. Despite recent characterization of genome-wide HIF DNA binding locations and hypoxia-regulated transcripts in different cell types, the molecular bases of HIF target selection remain unresolved. Herein, we combined multi-level experimental data and computational predictions to identify sequence motifs that may contribute to HIF target selectivity. We obtained a core set of bona fide HIF binding regions by integrating multiple HIF1 DNA binding and hypoxia expression profiling datasets. This core set exhibits evolutionarily conserved binding regions and is enriched in functional responses to hypoxia. Computational prediction of enriched transcription factor binding sites identified sequence motifs corresponding to several stress-responsive transcription factors, such as activator protein 1 (AP1), cAMP response element-binding (CREB), or CCAAT-enhancer binding protein (CEBP). Experimental validations on HIF-regulated promoters suggest a functional role of the identified motifs in modulating HIF-mediated transcription. Accordingly, transcriptional targets of these factors are over-represented in a sorted list of hypoxia-regulated genes. Altogether, our results implicate cooperativity among stress-responsive transcription factors in fine-tuning the HIF transcriptional response.
DescriptionThis is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.
Publisher version (URL)http://dx.doi.org/10.1371/journal.pone.0045708
URIhttp://hdl.handle.net/10261/57366
DOI10.1371/journal.pone.0045708
ISSN1932-6203
Appears in Collections:(IIBM) Artículos
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