Intricately Linked Transcriptional Activator and Repressor Functions of BRD4 in Regulation of Th2 Cell Differentiation

BET family protein BRD4 plays an important role in gene transcriptional regulation of T helper (Th) cell differentiation. While inhibition of the tandem bromodomains (BD1 and BD2) of BRD4 broadly inhibits differentiation of Th1, Th2, Th17 and Treg subtypes, selective BD1 inhibition affects mostly Th17 and to a lesser extent Th1 cells, suggesting distinct functions of BD1 and BD2 in Th cell lineage specific differentiation. However, the exact role of BRD4 in transcriptional regulation of Th2 differentiation has remained elusive. In this study, we report that in ex vivo lineage differentiation of mouse Th2 cells derived from mouse primary naive CD4 + T cells, Brd4 exerts dual functions through its BD2 domain in both facilitating transcriptional activation of Th2 key genes including Il4 , Il5 and Il13 , and repressing negative regulators such as Foxp3 and Fbxw7 . Importantly, we found that Brd4 plays no role in transcriptional expression of a key Th2 transcription factor Gata3 but inhibits protein degradation of Gata3 through direct transcriptional repression of Fbxw7 , an F box protein of the ubiquitin protein ligase complex. Our study provides previously unrecognized mechanistic insights into Brd4 dual functions in the control of both transcriptional activation and repression of genes important for Th2 cell differentiation.