Bmal1 regulates inflammatory responses in macrophages by modulating enhancer RNA transcription.
Bmal1 regulates inflammatory responses in macrophages by modulating enhancer RNA transcription.
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DOI：
10.1038/s41598-017-07100-3
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发表时间：
2017-08-01
影响因子：
4.6
通讯作者：
Manabe I
中科院分区：
文献类型：
--
作者：
Oishi Y;Hayashi S;Isagawa T;Oshima M;Iwama A;Shimba S;Okamura H;Manabe I
BMal1(由ARNTL基因编码)是一个核心的生物钟基因，它调控着参与昼夜节律的各种基因。尽管BMal1在巨噬细胞中有节律性地表达，但它在调节其细胞功能中的作用仍然不够清楚。在这里，我们报告了BMal1通过调节增强子活性来调节Toll样受体4(TLR4)激活后的时间依赖性炎症反应。整体转录组分析表明，ARNTL的缺失干扰了Kdo2脂蛋白A(Kla)激活TLR4所引起的时间依赖性炎症反应。虽然NF-κB p65的募集没有受到影响，但与野生型细胞相比，在含有PU1的增强子上，组蛋白3的赖氨酸27的乙酰化状态在−/−巨噬细胞中整体上增加了。在ARNTL−/−巨噬细胞中，抑制增强子表达的混合转录因子Nr1d1和Nr1d2的表达显著降低。此外，在混响依赖的Erna表达增强子上，ARNTL缺失增加了H3K27乙酰化水平。这些结果表明，BMal1控制KLA反应增强子，部分是通过调节混响指导的Erna转录。综上所述，本研究结果表明，含有BMal1的时钟转录因子网络通过调节增强子的表观遗传状态来控制巨噬细胞的炎症反应。
Bmal1 (encoded by Arntl gene) is a core circadian clock gene that regulates various genes involved in circadian rhythm. Although Bmal1 is expressed rhythmically in macrophages, the role of Bmal1 in the regulation of their cellular function remains insufficiently understood. Here, we report that Bmal1 regulates time-dependent inflammatory responses following Toll-like receptor 4 (TLR4) activation by modulating enhancer activity. Global transcriptome analysis indicated that deletion of Arntl perturbed the time-dependent inflammatory responses elicited by TLR4 activation by Kdo2-lipid A (KLA). Although the recruitment of NF-κB p65 was unaffected, the acetylation status of lysine 27 of histone 3, which correlates positively with enhancer activity, was globally increased at PU.1-containing enhancers in Arntl −/− macrophages as compared to wild-type cells. Expression of Nr1d1 and Nr1d2, encoding RevErb transcription factors, which repress enhancer RNA expression, was significantly decreased in Arntl −/− macrophages. Moreover, the level of H3K27 acetylation was increased by Arntl deletion at RevErb-dependent eRNA-expressing enhancers. These results suggest that Bmal1 controls KLA-responsive enhancers, in part by regulating RevErb-directed eRNA transcription. Taken together, the results of this study show that the clock transcription factor network containing Bmal1 controls the inflammatory responses of macrophages by regulating the epigenetic states of enhancers.
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DOI：
10.1038/nrm3949
发表时间：
2015-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
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作者：
Heinz S;Romanoski CE;Benner C;Glass CK
通讯作者：
Glass CK
DOI：
10.1126/science.1198125
发表时间：
2011-03-11
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
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通讯作者：
Lazar MA
DOI：
10.1073/pnas.1106750109
发表时间：
2012-01-10
影响因子：
11.1
作者：
Gibbs, Julie E.;Blaikley, John;Loudon, Andrew S. I.
通讯作者：
Loudon, Andrew S. I.
影响因子：
10.5
作者：
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通讯作者：
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影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK