Evolutionary conserved NSL complex/BRD4 axis controls transcription activation via histone acetylation
Evolutionary conserved NSL complex/BRD4 axis controls transcription activation via histone acetylation
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DOI：
10.1038/s41467-020-16103-0
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发表时间：
2020-05-07
影响因子：
16.6
通讯作者：
Akhtar, Asifa
中科院分区：
文献类型：
--
作者：
Gaub, Aline;Sheikh, Bilal N.;Akhtar, Asifa
细胞依赖于不同的基因库来维持稳态，但对其表达的转录网络仍知之甚少。含有MOF乙酰转移酶的非特异性致死（NSL）复合物是一种广泛的转录调节因子。它在果蝇中是必需的，人类KANSL 1亚基的单倍不足导致Koolen-de弗里斯综合征。在这里，我们进行了全基因组RNAi筛选，并确定BET蛋白BRD 4作为NSL复合物的进化保守辅因子。使用果蝇和小鼠胚胎干细胞，我们建立了一个招募层次，其中NSL沉积的组蛋白乙酰化使BRD 4招募组成型活性基因的转录。Koolen-de弗里斯患者来源的成纤维细胞中的转录组分析揭示了由NSL复合物/BRD 4轴诱发的细胞稳态特征的扰动。我们认为BRD 4代表了NSL复合物和转录激活之间的保守桥梁，并为理解它们在健康和疾病状态下的功能提供了新的视角。含MOF乙酰转移酶的非特异性致死（NSL）复合物是一种广泛的转录调节因子，其KANSL 1亚基的单倍不足导致人类Koolen-de弗里斯综合征。在这里，作者将BET蛋白BRD 4鉴定为NSL复合物的进化保守辅因子，并提供证据表明NSL沉积的组蛋白乙酰化诱导BRD 4募集用于组成型活性基因的转录。
Cells rely on a diverse repertoire of genes for maintaining homeostasis, but the transcriptional networks underlying their expression remain poorly understood. The MOF acetyltransferase-containing Non-Specific Lethal (NSL) complex is a broad transcription regulator. It is essential in Drosophila, and haploinsufficiency of the human KANSL1 subunit results in the Koolen-de Vries syndrome. Here, we perform a genome-wide RNAi screen and identify the BET protein BRD4 as an evolutionary conserved co-factor of the NSL complex. Using Drosophila and mouse embryonic stem cells, we characterise a recruitment hierarchy, where NSL-deposited histone acetylation enables BRD4 recruitment for transcription of constitutively active genes. Transcriptome analyses in Koolen-de Vries patient-derived fibroblasts reveals perturbations with a cellular homeostasis signature that are evoked by the NSL complex/BRD4 axis. We propose that BRD4 represents a conserved bridge between the NSL complex and transcription activation, and provide a new perspective in the understanding of their functions in healthy and diseased states. The MOF acetyltransferase-containing Non-Specific Lethal (NSL) complex is a broad transcription regulator and haploinsufficiency of its KANSL1 subunit results in the Koolen-de Vries syndrome in humans. Here, the authors identify the BET protein BRD4 as evolutionary conserved co-factor of the NSL complex and provide evidence that NSL-deposited histone acetylation induces BRD4 recruitment for transcription of constitutively active genes.