Hypoxia-inducible Factor-1 (HIF-1)-independent Hypoxia Response of the Small Heat Shock Protein hsp-16.1 Gene Regulated by Chromatin-remodeling Factors in the Nematode Caenorhabditis elegans
Hypoxia-inducible Factor-1 (HIF-1)-independent Hypoxia Response of the Small Heat Shock Protein hsp-16.1 Gene Regulated by Chromatin-remodeling Factors in the Nematode Caenorhabditis elegans
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DOI：
10.1074/jbc.m112.401554
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发表时间：
2013-01-18
影响因子：
4.8
通讯作者：
Lee, Junho
中科院分区：
文献类型：
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作者：
Lee, Jihyun;Lee, Junho
缺氧伴随着大量低氧反应基因的协同表达，其中许多基因受低氧诱导因子-1(HIF-1)的调控。然而，细胞对低氧的反应可能不是单独由HIF-1介导的，而且对HIF-1独立的低氧反应知之甚少。为了更好地建立HIF-1非依赖低氧反应的分子机制，我们试图表征线虫HSP-16.1基因低氧反应的分子基础；该基因已被证明是由低氧诱导的独立于HIF-1的。通过亲和纯化和LC-MS/MS鉴定，HMG-1.2是一种在低氧条件下与特定启动子区域结合的蛋白质。通过系统的预测，然后通过RNAi验证这些相互作用，我们确定染色质修饰物ISW-1和HDA-1、组蛋白H4和NURF-1染色质重塑因子是HIF-1非依赖性缺氧反应的新成分。这些数据表明，HSP-16.1启动子上核小体定位的调节可能在缺氧反应中起重要作用。此外，我们发现钙调神经磷酸酶不依赖于HIF-1来调节细胞对低氧的反应，在低氧条件下钙离子是诱导HSP-16.1所必需的。
Oxygen deprivation is accompanied by the coordinated expression of numerous hypoxia-responsive genes, many of which are controlled by hypoxia-inducible factor-1 (HIF-1). However, the cellular response to hypoxia is not likely to be mediated by HIF-1 alone, and little is known about HIF-1-independent hypoxia responses. To better establish the molecular mechanisms of HIF-1-independent hypoxia responses, we sought to characterize the molecular basis of the hypoxia response of the hsp-16.1 gene in the nematode Caenorhabditis elegans; this gene has been shown to be induced by hypoxia independently of hif-1. Using affinity purification followed by LC-MS/MS, we identified HMG-1.2 as a protein that binds to a specific promoter region under hypoxic conditions. By systematic prediction followed by validation of these interactions through RNAi, we identified the chromatin modifiers isw-1 and hda-1, histone H4, and NURF-1 chromatin-remodeling factors as new components of the hif-1-independent hypoxia response. These data suggest that the modulation of nucleosome positioning at the hsp-16.1 promoter may be important for the hypoxia response. In addition, we found that calcineurin acts independently of hif-1 to modulate the cellular response to hypoxia and that calcium ions are necessary for the induction of hsp-16.1 under hypoxic conditions.