Interrogating Histone Acetylation and BRD4 as Mitotic Bookmarks of Transcription
Vivek Behera,
Aaron J. Stonestrom,
Nicole Hamagami,
Chris C. Hsiung,
Cheryl A. Keller,
Belinda Giardine,
Simone Sidoli,
Zuo-Fei Yuan,
Natarajan V. Bhanu,
Michael T. Werner,
Hongxin Wang,
Benjamin A. Garcia,
Ross C. Hardison,
Gerd A. Blobel
Affiliations
Vivek Behera
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Aaron J. Stonestrom
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Nicole Hamagami
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Chris C. Hsiung
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Cheryl A. Keller
Department of Biochemistry and Molecular Biology, Penn State University, University Park, PA 16802, USA
Belinda Giardine
Department of Biochemistry and Molecular Biology, Penn State University, University Park, PA 16802, USA
Simone Sidoli
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA
Zuo-Fei Yuan
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA
Natarajan V. Bhanu
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA
Michael T. Werner
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Hongxin Wang
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Benjamin A. Garcia
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA
Ross C. Hardison
Department of Biochemistry and Molecular Biology, Penn State University, University Park, PA 16802, USA
Gerd A. Blobel
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
Summary: Global changes in chromatin organization and the cessation of transcription during mitosis are thought to challenge the resumption of appropriate transcription patterns after mitosis. The acetyl-lysine binding protein BRD4 has been previously suggested to function as a transcriptional “bookmark” on mitotic chromatin. Here, genome-wide location analysis of BRD4 in erythroid cells, combined with data normalization and peak characterization approaches, reveals that BRD4 widely occupies mitotic chromatin. However, removal of BRD4 from mitotic chromatin does not impair post-mitotic activation of transcription. Additionally, histone mass spectrometry reveals global preservation of most posttranslational modifications (PTMs) during mitosis. In particular, H3K14ac, H3K27ac, H3K122ac, and H4K16ac widely mark mitotic chromatin, especially at lineage-specific genes, and predict BRD4 mitotic binding genome wide. Therefore, BRD4 is likely not a mitotic bookmark but only a “passenger.” Instead, mitotic histone acetylation patterns may constitute the actual bookmarks that restore lineage-specific transcription patterns after mitosis. : Chromatin reader protein BRD4 is thought to bookmark mitotic chromatin to propagate transcriptional states across mitosis. Behera et al. profiled and perturbed mitotic BRD4 chromatin occupancy to show that BRD4 is dispensable for this process. Instead, BRD4 mitotic chromatin association is likely a mere reflection of mitotically stable histone marks. Keywords: erythroid cells, mitotic bookmarking, mitosis, cell identity, BRD4, histone marks
