BRD4 Deficiency Selectively Affects a Unique Developmental Subpopulation in Thymocytes

Abstract

The bromodomain protein BRD4 is a driver in both inflammatory diseases and cancers. It has multiple functions, contributing to chromatin structure and transcription through its intrinsic HAT and kinase activities. Despite the wide-ranging characterization of BRD4, little is known about its in vivo function. In the present study, we have examined the role of BRD4 in T cell development by conditional deletion at various stages of thymocyte differentiation. We found that BRD4 is critical for normal T cell development. Surprisingly, BRD4 selectively regulates the progression of immature CD8 single positive (ISP) thymocytes into quiescent DP thymocytes. In striking contrast, BRD4 deletion does not affect the extensive proliferation associated with the differentiation of double negative (DN) into ISP cells. Nor does it affect the maturation of double positive (DP) into conventional CD4+ and CD8+ thymocytes. These studies lead to the unexpected conclusion that BRD4 selectively regulates preselection ISP thymocytes.\n\nOn-line SummaryImmature CD8 single-positive (ISP) thymocytes are identified as a molecularly-distinct thymocyte subpopulation, dependent on BRD4 for progression to the DP stage. DN and DP are BRD4-independent. These findings provide new insights into BRD4, a therapeutic target in inflammation and cancer.