溴结构域蛋白 BRD4 与乙酰化组蛋白结合以调节转录。 BRD4 还可以促进癌细胞增殖。然而，BRD4 在正常细胞生长中的作用仍不清楚。在这里，我们通过使用条件性 Brd4 敲除 (KO) 的小鼠胚胎成纤维细胞来研究这个问题。我们发现 Brd4KO 细胞比野生型细胞生长更慢；它们无法完成复制，无法实现有丝分裂，并且在所有细胞周期阶段都表现出广泛的 DNA 损伤。 BRD4 是 450 多个细胞周期基因的表达所必需的，包括编码对基因组复制和染色体分离至关重要的核心组蛋白和着丝粒/动粒蛋白的基因。此外，我们发现许多控制 R 环形成和 DNA 损伤反应 (DDR) 的基因需要 BRD4 才能表达。最后，BRD4 组成型占据控制 R 环、DDR 和细胞周期进程的基因。总之，BRD4 在表观遗传上标记上述基因，并作为正常细胞生长的主调节因子。© 2024 由 Elsevier Inc. 出版。

Bromodomain protein BRD4 binds to acetylated histones to regulate transcription. BRD4 also drives cancer cell proliferation. However, the role of BRD4 in normal cell growth has remained unclear. Here, we investigated this 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. In summary, BRD4 epigenetically marks above genes and serves as a master regulator of normal cell growth.© 2024 Published by Elsevier Inc.