Department of Genetics, University of Cambridge, Downing Street, Cambridge, CB2 3EH, UK.
German Cancer Research Center-Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Nat Commun. 2021 Oct 7;12(1):5864. doi: 10.1038/s41467-021-26083-4.
Pausing of RNA polymerase II (Pol II) close to promoters is a common regulatory step in RNA synthesis, and is coordinated by a ribonucleoprotein complex scaffolded by the noncoding RNA RN7SK. The function of RN7SK-regulated gene transcription in adult tissue homoeostasis is currently unknown. Here, we deplete RN7SK during mouse and human epidermal stem cell differentiation. Unexpectedly, loss of this small nuclear RNA specifically reduces transcription of numerous cell cycle regulators leading to cell cycle exit and differentiation. Mechanistically, we show that RN7SK is required for efficient transcription of highly expressed gene pairs with bidirectional promoters, which in the epidermis co-regulated cell cycle and chromosome organization. The reduction in transcription involves impaired splicing and RNA decay, but occurs in the absence of chromatin remodelling at promoters and putative enhancers. Thus, RN7SK is directly required for efficient Pol II transcription of highly transcribed bidirectional gene pairs, and thereby exerts tissue-specific functions, such as maintaining a cycling cell population in the epidermis.
暂停 RNA 聚合酶 II（Pol II）接近启动子是 RNA 合成中常见的调控步骤，由非编码 RNA RN7SK 支架构成的核糖核蛋白复合物进行协调。目前尚不清楚 RN7SK 调节的基因转录在成人组织稳态中的功能。在这里，我们在小鼠和人类表皮干细胞分化过程中耗尽 RN7SK。出乎意料的是，这种小核 RNA 的缺失特异性降低了许多细胞周期调节剂的转录，导致细胞周期退出和分化。从机制上讲，我们表明 RN7SK 是高效转录具有双向启动子的高表达基因对所必需的，在表皮中，这些基因对共同调节细胞周期和染色体组织。转录减少涉及剪接和 RNA 衰变受损，但在启动子和推定增强子处不存在染色质重塑的情况下发生。因此，RN7SK 直接需要高效的 Pol II 转录高度转录的双向基因对，从而发挥组织特异性功能，例如维持表皮中的循环细胞群体。
