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.
| Original language | English (US) |
|---|---|
| Article number | e45708 |
| Journal | PLoS One |
| Volume | 7 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 24 2012 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Agricultural and Biological Sciences(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
Cooperativity of Stress-Responsive Transcription Factors in Core Hypoxia-Inducible Factor Binding Regions. / Villar, Diego; Ortiz-Barahona, Amaya; Gómez-Maldonado, Laura; Pescador, Nuria; Sánchez-Cabo, Fátima; Hackl, Hubert; Rodriguez, Benjamin A T; Trajanoski, Zlatko; Dopazo, Ana; Huang, Hui-ming; Yan, Pearlly S.; del Peso, Luis.
In: PLoS One, Vol. 7, No. 9, e45708, 24.09.2012.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cooperativity of Stress-Responsive Transcription Factors in Core Hypoxia-Inducible Factor Binding Regions
AU - Villar, Diego
AU - Ortiz-Barahona, Amaya
AU - Gómez-Maldonado, Laura
AU - Pescador, Nuria
AU - Sánchez-Cabo, Fátima
AU - Hackl, Hubert
AU - Rodriguez, Benjamin A T
AU - Trajanoski, Zlatko
AU - Dopazo, Ana
AU - Huang, Hui-ming
AU - Yan, Pearlly S.
AU - del Peso, Luis
PY - 2012/9/24
Y1 - 2012/9/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84866658759&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84866658759&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0045708
DO - 10.1371/journal.pone.0045708
M3 - Article
C2 - 23029193
AN - SCOPUS:84866658759
VL - 7
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 9
M1 - e45708
ER -