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Interrogating histone acetylation and BRD4 as mitotic bookmarks of transcription [Histones]

ABSTRACT: Global changes in chromatin organization and the cessation of transcription during mitosis are thought to challenge the resumption of appropriate transcription patterns following 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 novel 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE128161 | GEO | 2019/04/10

REPOSITORIES: GEO

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Project description:Javasky E, Shamir I, Gandhi S, Egri S, Sandler O, Rothbart SB, Kaplan N, Jaffe JD, Goren A, and Simon I. Genome Research 2018. Mitosis encompasses key molecular changes including chromatin condensation, nuclear envelope breakdown and reduced transcription levels. Immediately after mitosis, the interphase chromatin structure is reestablished and transcription resumes. The reestablishment of the interphase chromatin requires bookmarking, i.e., the retention of at least partial information during mitosis. Yet, while recent studies demonstrate that chromatin accessibility is generally preserved during mitosis and is only locally modulated, the exact details of the bookmarking process and its components are still unclear. To gain a deeper understanding of the mitotic bookmarking process, we merged proteomics, immunofluorescence, and ChIP-seq approaches to study the mitotic and interphase organization in human cells. We focused on key histone modifications, and employed the HeLa-S3 cells as a model system. Generally, we observed a global concordance between the genomic organization of histone modifications in interphase and mitosis, yet the abundance of the two types of modifications we investigated was different. Whereas histone methylation patterns remain highly similar, histone acetylation patterns show a general reduction while maintaining their genomic organization. In line with a recent study demonstrating that minimal transcription is retained during mitosis, we show that RNA polymerase II does not fully disassociate from the genome, but rather maintains its genomic localization at reduced levels. Next, we followed up on previous studies demonstrating that nucleosome depleted regions (NDRs) become occupied by a nucleosome during mitosis. Surprisingly, we observed that the nucleosome introduced into the NDR during mitosis encompasses a distinctive set of histone modifications, differentiating it from the surrounding nucleosomes. We show that the nucleosomes in the vicinity of the NDR appear to both shift into the NDR during mitosis and undergo deacetylation. HDAC inhibition by the small molecule TSA reverts the deacetylation pattern of the shifted nucleosome. Taken together, our results demonstrate that the epigenomic landscape can serve as a major component of the mitotic bookmarking process, and provide evidence for a mitotic deposition and deacetylation of the nucleosomes surrounding the NDR.

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Interrogating histone acetylation and BRD4 as mitotic bookmarks of transcription [Histones]

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