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Genome accessibility is widely preserved and locally modulated during mitosis [Dnase-seq]

ABSTRACT: Mitosis entails global alterations to chromosome structure and nuclear architecture, concomitant with transient silencing of transcription. How cells transmit transcriptional states through mitosis remains incompletely understood. While many nuclear factors dissociate from mitotic chromosomes, the observation that certain nuclear factors and chromatin features remain associated with individual loci during mitosis originated the hypothesis that they could provide transcriptional memory through mitosis. To obtain the first genome-wide view of the dynamics of chromatin structure during mitosis, we compared the DNase sensitivity of interphase and mitotic chromatin at two stages of cellular maturation in a rapidly dividingmurine erythroblastmodel. Despite global chromosome condensation visible during mitosis at the microscopic level, the chromatin accessibility landscape is largely unaltered. However, mitotic chromatin accessibility is locally dynamic, with individual loci maintaining none, some, or all of their interphase accessibility. Mitotic reduction in accessibility occurs primarily within narrow, highly hypersensitive sites that frequently coincide with transcription factor binding sites, whereas broader domains of moderate accessibility tend to be more stable. In mitosis, proximal promoters generally maintain their accessibility, whereas distal regulatory elements preferentially lose accessibility. Promoters with the highest degree of accessibility preservation in mitosis tend to also be accessible across many murine tissues in interphase. Transcription factor GATA1 exerts site-specific changes in interphase accessibility that are most pronounced at distal regulatory elements, but does not visibly influence mitotic accessibility. We conclude that features of open chromatin are remarkably stable through mitosis and are modulated at the level of individual genes and regulatory elements.

ORGANISM(S): Mus musculus

PROVIDER: GSE61885 | GEO | 2014/10/01

SECONDARY ACCESSION(S): PRJNA262621

REPOSITORIES: GEO

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Project description:Mitosis entails global alterations to chromosome structure and nuclear architecture, concomitant with transient silencing of transcription. How cells transmit transcriptional states through mitosis remains incompletely understood. While many nuclear factors dissociate from mitotic chromosomes, the observation that certain nuclear factors and chromatin features remain associated with individual loci during mitosis originated the hypothesis that they could provide transcriptional memory through mitosis. To obtain the first genome-wide view of the dynamics of chromatin structure during mitosis, we compared the DNase sensitivity of interphase and mitotic chromatin at two stages of cellular maturation in a rapidly dividingmurine erythroblastmodel. Despite global chromosome condensation visible during mitosis at the microscopic level, the chromatin accessibility landscape is largely unaltered. However, mitotic chromatin accessibility is locally dynamic, with individual loci maintaining none, some, or all of their interphase accessibility. Mitotic reduction in accessibility occurs primarily within narrow, highly hypersensitive sites that frequently coincide with transcription factor binding sites, whereas broader domains of moderate accessibility tend to be more stable. In mitosis, proximal promoters generally maintain their accessibility, whereas distal regulatory elements preferentially lose accessibility. Promoters with the highest degree of accessibility preservation in mitosis tend to also be accessible across many murine tissues in interphase. Transcription factor GATA1 exerts site-specific changes in interphase accessibility that are most pronounced at distal regulatory elements, but does not visibly influence mitotic accessibility. We conclude that features of open chromatin are remarkably stable through mitosis and are modulated at the level of individual genes and regulatory elements. Dnase-Seq data is integrated with Chip-seq [GSE36589, GSE30142] and RNA-seq to examine epigentic changes in mitosis. We performed DNase-seq on two cell lines, G1E and G1E-ER4, both on an asynchronus population, and on a sample of cells in mitosis; each of the 4 experiments in triplicate.

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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Genome accessibility is widely preserved and locally modulated during mitosis [Dnase-seq]

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