BRD4 is an epigenome reader known to exert key roles at the interface between chromatin remodeling and transcriptional regulation, and is primarily known for its role in promoting gene expression. In selective contexts, however, BRD4 may work as negative regulator of transcription. Here, we reported that BRD4 binds several long noncoding RNAs (lncRNA). Among these, the lncRNA NEAT1 was found to interfere with BRD4 transcriptional activity. Mechanistically, lncNEAT1 forms a complex with BRD4 and WDR5 and maintains them in a low-activity state. Treatment with Bromodomains and Extraterminal (BET) inhibitor caused the lncRNA NEAT1 to dissociate from the BRD4/WDR5 complex, restored the acetyl-transferase capacity of BRD4, and restored the availability of WDR5 to promote histone trimethylation, thereby promoting BRD4/WDR5 transcriptional activity and activation of target gene expression. In addition, the lncRNA NEAT1 then became available to bind and to inhibit EZH2, cooperatively increasing transcriptional activation. Implications: Our results revealed an epigenetic program that involves the interaction between the lncRNA NEAT1 and BRD4, functioning as a molecular switch between BRD4's activator and repressor chromatin complexes.

中文翻译：

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长链非编码 RNA NEAT1 作为 BRD4 转录活性的分子开关并介导 BRD4/WDR5 靶基因的抑制

BRD4 是一种表观基因组阅读器，已知在染色质重塑和转录调控之间的界面发挥关键作用，并且主要以其在促进基因表达中的作用而闻名。然而，在选择性环境中，BRD4 可能作为转录的负调节因子。在这里，我们报道了 BRD4 结合了几种长的非编码 RNA (lncRNA)。其中，发现 lncRNA NEAT1 干扰 BRD4 转录活性。从机制上讲，lncNEAT1 与 BRD4 和 WDR5 形成复合物，并将它们保持在低活性状态。Bromodomains 和 Extraterminal (BET) 抑制剂处理导致 lncRNA NEAT1 从 BRD4/WDR5 复合物中解离，恢复 BRD4 的乙酰转移酶能力，并恢复 WDR5 的可用性以促进组蛋白三甲基化，从而促进 BRD4/WDR5 转录活性和靶基因表达的激活。此外，lncRNA NEAT1 随后可用于结合和抑制 EZH2，协同增加转录激活。启示：我们的研究结果揭示了一个表观遗传程序，该程序涉及 lncRNA NEAT1 和 BRD4 之间的相互作用，充当 BRD4 的激活剂和阻遏染色质复合物之间的分子开关。