The BET Family Member BRD4 Interacts with OCT4 and Regulates Pluripotency Gene Expression

Embryonic stem cell (ESC) pluripotency is controlled by defined transcription factors. During cellular differentiation, ESCs undergo a global epigenetic reprogramming. Female ESCs exemplify this process as one of the two X-chromosomes is globally silenced during X chromosome inactivation (XCI) to balance the X-linked gene disparity with XY males. The pluripotent factor OCT4 regulates XCI by triggering X chromosome pairing and counting. OCT4 directly binds Xite and Tsix, which encode two long noncoding RNAs (lncRNAs) that suppress the silencer lncRNA, Xist. To control its activity as a master regulator in pluripotency and XCI, OCT4 must have chromatin protein partners. Here we show that BRD4, a member of the BET protein subfamily, interacts with OCT4. BRD4 occupies the regulatory regions of pluripotent genes and the lncRNAs of XCI. BET inhibition or depletion of BRD4 reduces the expression of many pluripotent genes and shifts cellular fate showing that BRD4 is pivotal for transcription in ESCs. •OCT4 interacts with BRD4 in embryonic stem cells (ESCs)•BRD4 occupies the regulatory regions of pluripotent genes•BRD4 occupies and controls the lncRNAs in X chromosome inactivation•BET inhibition or depletion of BRD4 in ESCs shifts cell fate away from pluripotency OCT4 is a master regulator of pluripotency in embryonic stem cells (ESCs). In this article, Donohoe and colleagues show that OCT4 interacts with the BET family member BRD4. BRD4 occupies the genes controlling pluripotency, and the long noncoding RNAs regulating female X chromosome inactivation. Inhibition or loss of BRD4 shifts ESC fate from pluripotency to neuroectoderm. Inhibition of the BRD4 partner P-TEFb blocks gene activity in ESCs. BRD4 is pivotal for gene transcription in ESCs.