Bromodomain protein BRD4 directs mitotic cell division of mouse fibroblasts by inhibiting DNA damage
Tiyun Wu,
Haitong Hou,
Anup Dey,
Mahesh Bachu,
Xiongfong Chen,
Jan Wisniewski,
Fuki Kudoh,
Chao Chen,
Sakshi Chauhan,
Hua Xiao,
Richard Pan,
Keiko Ozato
Affiliations
Tiyun Wu
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
Haitong Hou
Science Center for Future Foods, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China
Anup Dey
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
Mahesh Bachu
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA; Weill Cornell Medicine, Graduate School of Medical Sciences, 1300 York Avenue Box 65, New York, NY 10065, USA
Xiongfong Chen
CCR-SF Bioinformatics Group, Advanced Biomedical and Computational Sciences, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
Jan Wisniewski
Confocal Microscopy and Digital Imaging Facility, Experimental Immunology Branch, CCR, NCI NIH Bldg 10 Rm 4A05, Bethesda, MD 20892, USA
Fuki Kudoh
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
Chao Chen
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA; Division of Hematology/Oncology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
Sakshi Chauhan
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
Hua Xiao
Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Richard Pan
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
Keiko Ozato
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA; Corresponding author
Summary: 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.
