The Mechanism And Function Of BRD7in TGF-β Signaling

The transforming growth factor-β (TGF-β) signaling plays an important role in cellular proliferation, differentiation, apoptosis and embryonic development. TGF-P is implicated in various human diseases. Smads are key signal transducers for TGF-β signaling and are grouped into three classes:receptor-regulated Smads (R-Smads), common mediator Smad (Co-Smad, Smad4), inhibitory Smads (I-Smads). Among them, Smad4is the core factor shared by all branches of TGF-β superfamily signaling. Upon TGF-β stimulation the Smad4-R-Smads complex translocates into the nucleus to mediate the transcripiton of TGF-β target genes.BRD7(bromodomain containing7) was firstly identified from the array of nasopharyngeal carcinoma cells comparing to normal cells. It is a subunit of SWI/SNF complexes which play a role in chromatin remodeling through bromodomain. Previous studies report that BRD7could regulate WNT, ras/MEK/ERK and Rb/E2F pathways. But there is no evidence that BRD7participates in TGF-β signaling.Using yeast-two hybrid screening system, we identified BRD7as a binding partner with Smad4. We confirmed the interaction in vivo and in vitro and then mapped the interaction domains of the two proteins. Through transcriptional reporter assays we found that BRD7enhanced the expression of TGF-β-induced target genes and promoted TGF-P signaling. We demonstrated that BRD7potentiates TGF-β signaling pathway by acting as a Smad4co-transcriptional activator that enhances DNA binding ability of Smad4through the interaction between BRD7-bromodomain and acetylated-H3K9. Meanwhile, BRD7promotes transcriptional activity of Smad4through the histone acetyltransferase p300. BRD7consequently influences TGF-β-involved cellular processes including cell proliferation, cell cycle and EMT.In summary, BRD7mediates TGF-P signaling through the interaction with Smad4. Our finding not only provides insights into understanding of how the Smads complex acts in transcription to mediate TGF-β signaling, but also implicates a potential role of BRD7in regulating tumor.