BRD4结合乙酰化组蛋白以调控转录和驱动癌细胞增殖。然而，BRD4在正常细胞生长中的作用仍有待阐明。在本研究中，我们使用具有条件性Brd4基因敲除模式的小鼠胚胎成纤维细胞来探究这个问题。我们发现Brd4敲除细胞的生长速度比野生型细胞慢：它们无法完成复制，无法达到有丝分裂，并且在所有细胞周期阶段都出现广泛的DNA损伤。BRD4在450多个细胞周期基因的表达中起到了重要作用，包括编码核心组蛋白和中心体/着丝粒蛋白的基因，这些基因对基因组复制和染色体分离至关重要。此外，我们还表明，多个控制R环形结构形成和DNA损伤响应的基因需要BRD4来进行表达。最后，BRD4在控制R环形结构、DNA损伤响应和细胞周期进程的基因上有持续的作用。我们认为，BRD4通过表观遗传地标记这些基因，并充当正常细胞生长的主要调控因子。

BRD4 binds to acetylated histones to regulate transcription and drive cancer cell proliferation. However, the role of BRD4 in normal cell growth remains to be elucidated. Here we investigated the question by using mouse embryonic fibroblasts with conditional Brd4 knockout (KO). We found that Brd4KO cells grow more slowly than wild type cells: they do not complete replication, fail to achieve mitosis, and exhibit extensive DNA damage throughout all cell cycle stages. BRD4 was required for expression of more than 450 cell cycle genes including genes encoding core histones and centromere/kinetochore proteins that are critical for genome replication and chromosomal segregation. Moreover, we show that many genes controlling R-loop formation and DNA damage response (DDR) require BRD4 for expression. Finally, BRD4 constitutively occupied genes controlling R-loop, DDR and cell cycle progression. We suggest that BRD4 epigenetically marks those genes and serves as a master regulator of normal cell growth.