Genome-wide identification of hypoxia-inducible factor binding sites and target genes by a probabilistic model integrating transcription-profiling data and in silico binding site prediction.
Genome-wide identification of hypoxia-inducible factor binding sites and target genes by a probabilistic model integrating transcription-profiling data and in silico binding site prediction.
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DOI：
10.1093/nar/gkp1205
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发表时间：
2010-04
影响因子：
14.9
通讯作者：
del Peso L
中科院分区：
文献类型：
--
作者：
Ortiz-Barahona A;Villar D;Pescador N;Amigo J;del Peso L
缺氧诱导因子（HIF）驱动的转录反应是适应氧限制的核心。因此，HIF靶点的完整鉴定对于理解细胞对缺氧的反应至关重要。在此，我们描述了一种基于系统发育足迹和转录谱荟萃分析相结合的计算策略，用于鉴定hif靶基因。将所得候选基因与已发表的HIF1a全基因组染色质免疫沉淀法进行比较，结果表明具有较高的灵敏度（78%）和特异性（97.8%）。为了验证我们的策略，我们在一组假定的靶点上进行了HIF1a染色质免疫沉淀。我们的研究结果证实了计算策略在预测HIF结合位点方面的稳健性，并揭示了几个新的HIF靶点，包括re1沉默转录因子协同抑制因子（RCOR2）。此外，将描述的多态性映射到预测的HIF结合位点，确定了几个可能改变HIF结合的单核苷酸多态性（snp）。作为原理证明，我们证明SNP rs17004038，定位于巨噬细胞迁移抑制因子（MIF）位点的功能性缺氧反应元件，阻止缺氧诱导该基因。总之，我们的研究结果表明，所提出的策略是识别HIF直接靶点的有力工具，扩展了我们对细胞缺氧适应的认识，并为这种反应的个体间差异提供了线索。
The transcriptional response driven by Hypoxia-inducible factor (HIF) is central to the adaptation to oxygen restriction. Hence, the complete identification of HIF targets is essential for understanding the cellular responses to hypoxia. Herein we describe a computational strategy based on the combination of phylogenetic footprinting and transcription profiling meta-analysis for the identification of HIF-target genes. Comparison of the resulting candidates with published HIF1a genome-wide chromatin immunoprecipitation indicates a high sensitivity (78%) and specificity (97.8%). To validate our strategy, we performed HIF1a chromatin immunoprecipitation on a set of putative targets. Our results confirm the robustness of the computational strategy in predicting HIF-binding sites and reveal several novel HIF targets, including RE1-silencing transcription factor co-repressor (RCOR2). In addition, mapping of described polymorphisms to the predicted HIF-binding sites identified several single-nucleotide polymorphisms (SNPs) that could alter HIF binding. As a proof of principle, we demonstrate that SNP rs17004038, mapping to a functional hypoxia response element in the macrophage migration inhibitory factor (MIF) locus, prevents induction of this gene by hypoxia. Altogether, our results show that the proposed strategy is a powerful tool for the identification of HIF direct targets that expands our knowledge of the cellular adaptation to hypoxia and provides cues on the inter-individual variation in this response.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
2.7
作者：
Guimbellot JS;Erickson SW;Mehta T;Wen H;Page GP;Sorscher EJ;Hong JS
通讯作者：
Hong JS
影响因子：
14.9
作者：
Chen KF;Lai YY;Sun HS;Tsai SJ
通讯作者：
Tsai SJ
影响因子：
4.3
作者：
Hoek, Keith S.;Schlegel, Natalie C.;Steingrimsson, Eirikur
通讯作者：
Steingrimsson, Eirikur
影响因子：
0.7
作者：
Alonso, M. Eva;Pernaute, Barbara;Manzanares, Miguel
通讯作者：
Manzanares, Miguel