High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq
High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq
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DOI：
10.1182/blood-2010-10-314427
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发表时间：
2011-06-09
期刊：
影响因子：
20.3
通讯作者：
Mole, David R.
中科院分区：
文献类型：
--
作者：
Schoedel, Johannes;Oikonomopoulos, Spyros;Mole, David R.
低氧诱导因子(HIF)调节所有哺乳动物细胞对氧分压变化作出反应的主要转录级联反应。表达阵列表明，数百个基因受到这一途径的调控，控制着不同的过程，这些过程反过来又协调了氧气的输送和利用。然而，HIF对基因表达的直接和间接控制的程度以及决定HIF调控基因范围的因素仍然不清楚。使用与高通量测序相关联的染色质免疫沉淀，我们确定了整个基因组中的HIF结合位点，而不依赖于基因结构。利用基因集浓缩分析，我们证明了与HIF对基因表达的调控有很强的相关性，表明这些位点在较长的基因组间隔内运行。对HIF结合基序的分析表明，在核心RCGTG结合基序之外的序列偏好，但没有揭示任何额外的绝对序列要求。在整个基因组中，只有一小部分潜在结合位点被HIF结合，尽管潜在结合位点在常氧DNase1超敏位点的占有率增加了约20倍(与启动子的距离无关)，这表明染色质的表观遗传调控可能在定义对低氧的反应中发挥重要作用。(血。2011年；117(23)：e207-e217)
Hypoxia-inducible factor (HIF) regulates the major transcriptional cascade central to the response of all mammalian cells to alterations in oxygen tension. Expression arrays indicate that many hundreds of genes are regulated by this pathway, controlling diverse processes that in turn orchestrate both oxygen delivery and utilization. However, the extent to which HIF exerts direct versus indirect control over gene expression together with the factors dictating the range of HIF-regulated genes remains unclear. Using chromatin immunoprecipitation linked to high throughput sequencing, we identify HIF-binding sites across the genome, independently of gene architecture. Using gene set enrichment analysis, we demonstrate robust associations with the regulation of gene expression by HIF, indicating that these sites operate over long genomic intervals. Analysis of HIF-binding motifs demonstrates sequence preferences outside of the core RCGTG-binding motif but does not reveal any additional absolute sequence requirements. Across the entire genome, only a small proportion of these potential binding sites are bound by HIF, although occupancy of potential sites was enhanced approximately 20-fold at normoxic DNAse1 hypersensitivity sites (irrespective of distance from promoters), suggesting that epigenetic regulation of chromatin may have an important role in defining the response to hypoxia. (Blood. 2011;117(23):e207-e217)