Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis.
Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis.
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DOI：
10.1093/nar/gkq212
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发表时间：
2010-09
影响因子：
14.9
通讯作者：
Biswal S
中科院分区：
文献类型：
--
作者：
Malhotra D;Portales-Casamar E;Singh A;Srivastava S;Arenillas D;Happel C;Shyr C;Wakabayashi N;Kensler TW;Wasserman WW;Biswal S
Nrf 2（核因子E2 p45相关因子2）转录因子响应于不同的氧化和亲电子环境压力，通过规避Keap 1的抑制，易位到细胞核，并激活细胞保护基因。nrf 2反应在小鼠模型中提供针对化学致癌、慢性炎症、神经变性、肺气肿、哮喘和败血症的保护。nrf 2调节大量基因的表达，这些基因可以使氧化剂和亲电子物质解毒，并修复或去除受损的大分子，例如通过蛋白酶体加工。然而，Nrf 2的许多直接靶点仍然不确定。在这里，小鼠胚胎成纤维细胞（MEF）的组成性核积累（Keap 1-/-）或耗尽（Nrf 2-/-）的Nrf 2被用来进行染色质免疫沉淀与平行测序（ChIP-Seq）和全球转录谱。这个独特的Nrf 2 ChIP-Seq数据集高度富集了Nrf 2结合基序。整合ChIP-Seq和微阵列分析，我们确定了Nrf 2的645个基础和654个诱导型直接靶点，其中244个基因位于交叉点。应激反应和细胞增殖中的调节途径区分了诱导型和基础型程序。结果在香烟烟雾暴露小鼠的体内应激模型中得到证实。这项研究揭示了Nrf 2应激反应的全局电路，强调Nrf 2作为细胞存活反应的中心节点。
The Nrf2 (nuclear factor E2 p45-related factor 2) transcription factor responds to diverse oxidative and electrophilic environmental stresses by circumventing repression by Keap1, translocating to the nucleus, and activating cytoprotective genes. Nrf2 responses provide protection against chemical carcinogenesis, chronic inflammation, neurodegeneration, emphysema, asthma and sepsis in murine models. Nrf2 regulates the expression of a plethora of genes that detoxify oxidants and electrophiles and repair or remove damaged macromolecules, such as through proteasomal processing. However, many direct targets of Nrf2 remain undefined. Here, mouse embryonic fibroblasts (MEF) with either constitutive nuclear accumulation (Keap1−/−) or depletion (Nrf2−/−) of Nrf2 were utilized to perform chromatin-immunoprecipitation with parallel sequencing (ChIP-Seq) and global transcription profiling. This unique Nrf2 ChIP-Seq dataset is highly enriched for Nrf2-binding motifs. Integrating ChIP-Seq and microarray analyses, we identified 645 basal and 654 inducible direct targets of Nrf2, with 244 genes at the intersection. Modulated pathways in stress response and cell proliferation distinguish the inducible and basal programs. Results were confirmed in an in vivo stress model of cigarette smoke-exposed mice. This study reveals global circuitry of the Nrf2 stress response emphasizing Nrf2 as a central node in cell survival response.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
7
作者：
Euskirchen, Ghia M.;Rozowsky, Joel S.;Snyder, Michael
通讯作者：
Snyder, Michael
影响因子：
14.8
作者：
Huang, Da Wei;Sherman, Brad T.;Lempicki, Richard A.
通讯作者：
Lempicki, Richard A.
影响因子：
4.8
作者：
Lee, JM;Li, J;Johnson, JA
通讯作者：
Johnson, JA
影响因子：
5.3
作者：
Katsuoka, F;Motohashi, H;Yamamoto, M
通讯作者：
Yamamoto, M