Regulation of BRD4 Function

Division Of Basic Sciences - Nci

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Abstract

BRD4 plays a critical role in numerous cancers and is an actively pursued therapeutic target. Notably, BRD4 has pleiotropic functions: it has a kinase activity that regulates transcription and a histone acetyl transferase (HAT) activity that regulates chromatin structure. Chromatin-bound BRD4 lacks kinase activity, and RNA Pol II-bound BRD4 exhibits no HAT activity. The mechanisms governing the switching of its functions from a chromatin to transcriptional regulator were not known previously. We have now found that these two enzymatic activities are cross-regulated, ensuring that only one is active at a time and further that the conversion between BRD4's functions is controlled by its phosphorylation at 3 specific sites by the JNK kinase. Thus, in addition to providing a new mechanistic understanding of BRD4 multifunctionality, this study also provides new insights into the understudied field of "moonlighting proteins" - proteins with multiple functions - and their regulation. Our studies reveal one mechanism underlying BRD4's functional switch. In response to diverse stimuli, JNK-mediated phosphorylation of human BRD4 at Thr1186 and Thr1212 triggers its transient release from chromatin, disrupting its HAT activity and potentiating its transcription-promoting kinase activity. BRD4 release from chromatin is necessary to toggle between its enzymatic activities: chromatin-bound BRD4 is kinase inactive and RNA Pol II-bound BRD4 does not acetylate chromatin. Released BRD4 directly interacts with and phosphorylates Pol II, PTEFb, and c-MYC, thereby promoting transcription of target genes involved in immune and inflammatory responses. JNK-mediated BRD4 functional switching induces CD8 expression in thymocytes and epithelial-to-mesenchymal transition (EMT) in prostate cancer cells. Interestingly, the phosphatase, PP4, dephosphorylates JNK phosphorylated BRD4 in the nucleoplasm, which is required to promotes its interaction with RNA Pol II at transcriptionally active sites. These findings elucidate the mechanism by which BRD4 transitions from a chromatin regulator to a transcriptional activator.