title: Cooperativity of stress-responsive transcription factors in core hypoxia-inducible factor binding regions.
abstract: The 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.
authors.affiliation: Department of Biochemistry, Universidad Autónoma de Madrid and Instituto de Investigaciones Biomedicas Alberto Sols, Madrid, Spain. dvillar@iib.uam.es
authors.forename: Diego
authors.initials: D
authors.lastname: Villar
authors.forename: Amaya
authors.initials: A
authors.lastname: Ortiz-Barahona
authors.forename: Laura
authors.initials: L
authors.lastname: Gómez-Maldonado
authors.forename: Nuria
authors.initials: N
authors.lastname: Pescador
authors.forename: Fátima
authors.initials: F
authors.lastname: Sánchez-Cabo
authors.forename: Hubert
authors.initials: H
authors.lastname: Hackl
authors.forename: Benjamin A T
authors.initials: BA
authors.lastname: Rodriguez
authors.forename: Zlatko
authors.initials: Z
authors.lastname: Trajanoski
authors.forename: Ana
authors.initials: A
authors.lastname: Dopazo
authors.forename: Tim H M
authors.initials: TH
authors.lastname: Huang
authors.forename: Pearlly S
authors.initials: PS
authors.lastname: Yan
authors.forename: Luis
authors.initials: L
authors.lastname: Del Peso
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000737:chemistry; D020869:Gene Expression Profiling; D006367:HeLa Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D013312:Stress, Physiological; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D051793:Hypoxia-Inducible Factor 1; D014157:Transcription Factors; D004247:DNA