JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states.
JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states.
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DOI：
10.1080/15592294.2018.1469891
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Umehara T
中科院分区：
文献类型：
--
作者：
Handoko L;Kaczkowski B;Hon CC;Lizio M;Wakamori M;Matsuda T;Ito T;Jeyamohan P;Sato Y;Sakamoto K;Yokoyama S;Kimura H;Minoda A;Umehara T
溴结构域和额外末端结构域 (BET) 蛋白是治疗癌症和免疫疾病的有希望的药物靶点。然而，与 BRD2 相比，在含溴结构域蛋白 4 (BRD4) 的背景下对 BET 抑制作用的研究更多，并且在全基因组水平上尚不清楚 BET 蛋白与组蛋白 H4-超乙酰化染色质的关联。在这里，我们报告了人类非小细胞肺癌 (NSCLC) 细胞系 H23 中 ChIP-seq 和转录组图谱的转录起始位点 (TSS) 分辨率综合分析。我们发现，组蛋白 H4 (H4K5acK8ac) 在 K5 和 K8 处的二乙酰化与大多数活性增强子和启动子中的 H3K27ac 和 BRD2 共定位，其中 BRD2 与 H4K5acK8ac 的关联性强于 H3K27ac。尽管 JQ1 的 BET 抑制导致 BRD2 与染色质的结合完全减少，但仅观察到 H4K5acK8ac 水平的局部变化，表明 BRD2 的募集不会影响整体组蛋白 H4 超乙酰化水平。这一发现支持了一个模型，其中通过组蛋白 H4 超乙酰化招募 BET 蛋白比 BET 蛋白相关乙酰转移酶对组蛋白 H4 的超乙酰化占主导地位。此外，我们发现大量 BRD2 结合基因，包括 MYC 及其下游靶基因，在 JQ1 处理后转录上调。使用 BRD2 富集位点和转录活性分析，我们确定了可能以 BRD2 依赖和独立方式参与 JQ1 反应的候选转录因子。
The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed, suggesting that recruitment of BRD2 does not influence global histone H4 hyperacetylation levels. This finding supports a model in which recruitment of BET proteins via histone H4 hyperacetylation is predominant over hyperacetylation of histone H4 by BET protein-associated acetyltransferases. In addition, we found that a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and -independent manner.
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DOI：
10.1126/science.1249830
发表时间：
2014-10-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baud MGJ;Lin-Shiao E;Cardote T;Tallant C;Pschibul A;Chan KH;Zengerle M;Garcia JR;Kwan TT;Ferguson FM;Ciulli A
通讯作者：
Ciulli A
影响因子：
4.6
作者：
Baker EK;Taylor S;Gupte A;Sharp PP;Walia M;Walsh NC;Zannettino AC;Chalk AM;Burns CJ;Walkley CR
通讯作者：
Walkley CR
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1007/s10577-015-9486-4
发表时间：
2015-12
期刊：
Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology
影响因子：
--
作者：
Hayashi-Takanaka Y;Maehara K;Harada A;Umehara T;Yokoyama S;Obuse C;Ohkawa Y;Nozaki N;Kimura H
通讯作者：
Kimura H
影响因子：
5.8
作者：
Akalin, Altuna;Franke, Vedran;Schuebeler, Dirk
通讯作者：
Schuebeler, Dirk