The bromodomain protein BRD4 regulates splicing during heat shock.
The bromodomain protein BRD4 regulates splicing during heat shock.
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DOI：
10.1093/nar/gkw729
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发表时间：
2017-01-09
影响因子：
14.9
通讯作者：
Schweiger MR
中科院分区：
文献类型：
--
作者：
Hussong M;Kaehler C;Kerick M;Grimm C;Franz A;Timmermann B;Welzel F;Isensee J;Hucho T;Krobitsch S;Schweiger MR
细胞对热应激的反应是一种古老的、进化上高度保守的防御机制，其特征在于细胞保护基因的转录上调和剪接的部分抑制。这些特征与肿瘤发展过程中的蛋白毒性应激反应非常相似。布罗莫结构域蛋白BRD4已被鉴定为氧化应激以及炎症反应的组成成员，主要是由于其在转录调控过程中的作用。此外，还有几条证据表明BRD4参与了剪接过程。使用RNA测序，我们发现在BRD4耗尽的细胞中热处理后，剪接抑制，特别是内含子保留（IR）显著增加。这导致受影响的转录物的mRNA表达减少，最可能是由于过早终止密码子。随后的实验表明，BRD4与热休克因子1（HSF 1）相互作用，使得在热应激下，BRD4被募集到核应激体，并且非编码SatIII RNA转录物被上调。这些发现暗示BRD4是热应激过程中剪接的重要调节因子。我们的数据将BRD4与应激诱导的剪接过程联系起来，这可能提供BRD4抑制剂在抗癌治疗方面的新机制。
The cellular response to heat stress is an ancient and evolutionarily highly conserved defence mechanism characterised by the transcriptional up-regulation of cyto-protective genes and a partial inhibition of splicing. These features closely resemble the proteotoxic stress response during tumor development. The bromodomain protein BRD4 has been identified as an integral member of the oxidative stress as well as of the inflammatory response, mainly due to its role in the transcriptional regulation process. In addition, there are also several lines of evidence implicating BRD4 in the splicing process. Using RNA-sequencing we found a significant increase in splicing inhibition, in particular intron retentions (IR), following heat treatment in BRD4-depleted cells. This leads to a decrease of mRNA abundancy of the affected transcripts, most likely due to premature termination codons. Subsequent experiments revealed that BRD4 interacts with the heat shock factor 1 (HSF1) such that under heat stress BRD4 is recruited to nuclear stress bodies and non-coding SatIII RNA transcripts are up-regulated. These findings implicate BRD4 as an important regulator of splicing during heat stress. Our data which links BRD4 to the stress induced splicing process may provide novel mechanisms of BRD4 inhibitors in regard to anti-cancer therapies.