Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy.
Mol Cancer Res. 2021 May;19(5):799-811. doi: 10.1158/1541-7786.MCR-20-0324. Epub 2021 Feb 5.
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 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 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 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 and BRD4, functioning as a molecular switch between BRD4's activator and repressor chromatin complexes.
BRD4 是一种已知在染色质重塑和转录调控之间发挥关键作用的表观基因组读取器，主要因其促进基因表达的作用而为人所知。然而，在选择性情况下，BRD4 可能作为转录的负调节剂发挥作用。在这里，我们报告 BRD4 结合了几种长非编码 RNA（lncRNA）。在这些之中，发现 lncRNA 干扰 BRD4 的转录活性。从机制上讲，lncNEAT1 与 BRD4 和 WDR5 形成复合物，并将它们维持在低活性状态。用溴结构域和末端（BET）抑制剂处理会导致 lncRNA 与 BRD4/WDR5 复合物解离，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 随后可与 EZH2 结合并抑制其功能，协同增加转录激活。意义：我们的结果揭示了一个涉及 lncRNA 和 BRD4 相互作用的表观遗传程序，作为 BRD4 的激活剂和抑制剂染色质复合物之间的分子开关。
