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Summary: The pluripotent state of embryonic stem cells (ESCs) is defined by its transcriptome and epigenome. The chromatin reader Brd4 determines ESC identity. Although Brd4 regulation in gene transcription has been well described, its contribution to the chromatin landscape is less known. Here, we show that Brd4’s bromodomains partner with the histone acetyltransferase P300, increasing its enzymatic activities. Augmenting histone acetylation by Brd4-P300 interaction recruits the chromatin remodeler Brg1 altering chromatin structure. This pathway is important for maintaining the expression and chromatin patterns of pluripotency-associated genes, such as Oct4, Nanog, and the X chromosome regulatory long noncoding RNAs Tsix and Xite. Furthermore, we show that the Brd4-P300 interaction regulates the de novo formation of chromatin marks during ESC differentiation, as exemplified by controlling the master regulators of mesoderm formation. Collectively, we delineate the function of Brd4 in organizing the chromatin structure that contributes to gene transcriptional regulation and cell fate determination. : Wu et al. find that Brd4’s bromodomains partner with the histone acetyltransferase P300 to augment its enzymatic activity. Brd4-P300 interaction recruits Brg1 to modify chromatin structure of pluripotency-associated genes in embryonic stem cells. Keywords: embryonic stem cells, pluripotency, BRD4, bromodomains, X-chromosome inactivation, Oct4, P300, acetylation, Brg1, chromatin