Impaired histone inheritance promotes tumor progression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE201262 | GEO | 2023/05/15
REPOSITORIES: GEO
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Project description:Chromatin-based epigenetic memory relies on the accurate distribution of parental histone tetramers to newly replicated DNA strands, serving as templates for chromatin structure duplication. Mcm2, a subunit of the replicative helicase, and the Dpb3/4, subunits of polymerase epsilon, govern parental histone deposition to the lagging and leading strands, respectively. However, their contribution to epigenetic inheritance remains controversial. Here we show in fission yeast that a Mcm2 histone chaperone mutation severely disrupts heterochromatin inheritance, while Dpb3/4 mutations cause only moderate defects. Surprisingly, simultaneous Mcm2 and Dpb3/4 mutations stabilizes heterochromatin inheritance. eSPAN analyses confirm the conservation of Mcm2 and Dpb3/4 functions in parental histone segregation, with their collective absence reducing segregation bias. Furthermore, the FACT histone chaperone also regulates parental histone transfer independently of strands and collaborates with Mcm2 and Dpb3/4 to maintain parental histone density, ensuring faithful heterochromatin inheritance. These results underscore the importance of precise parental histone segregation to the lagging strand for epigenetic inheritance and unveil unique properties of parental histone chaperones during DNA replication.
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Project description:Modified parental histones are segregated symmetrically to daughter DNA strands during replication and inherited through mitosis. How this may sustain the epigenome and cell identity remains unknown. Here, we show that transmission of histone-based information during replication maintains epigenome fidelity and embryonic stem cell plasticity. Asymmetric segregation of parental histones H3-H4 in MCM2-2A mutants compromised mitotic inheritance of histone modifications and globally altered the epigenome. This included widespread spurious deposition of repressive modifications, suggesting elevated epigenetic noise. Moreover, H3K9me3 loss at repeats caused de-repression and H3K27me3 redistribution across bivalent promoters correlated with misexpression of developmental genes. MCM2-2A mutation challenged dynamic transitions in cellular states across the cell cycle, enhancing naïve pluripotency and reducing lineage priming in G1. Further, developmental competence was diminished, correlating with impaired exit from pluripotency. Collectively, this argues that epigenetic inheritance of histone modifications maintains a correctly balanced and dynamic chromatin landscape able to support mammalian differentiation.
2023-06-15 | GSE154391 | GEO
Project description:Modified parental histones are segregated symmetrically to daughter DNA strands during replication and inherited through mitosis. How this may sustain the epigenome and cell identity remains unknown. Here, we show that transmission of histone-based information during replication maintains epigenome fidelity and embryonic stem cell plasticity. Asymmetric segregation of parental histones H3-H4 in MCM2-2A mutants compromised mitotic inheritance of histone modifications and globally altered the epigenome. This included widespread spurious deposition of repressive modifications, suggesting elevated epigenetic noise. Moreover, H3K9me3 loss at repeats caused de-repression and H3K27me3 redistribution across bivalent promoters correlated with misexpression of developmental genes. MCM2-2A mutation challenged dynamic transitions in cellular states across the cell cycle, enhancing naïve pluripotency and reducing lineage priming in G1. Further, developmental competence was diminished, correlating with impaired exit from pluripotency. Collectively, this argues that epigenetic inheritance of histone modifications maintains a correctly balanced and dynamic chromatin landscape able to support mammalian differentiation.
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Project description:Modified parental histones are segregated symmetrically to daughter DNA strands during replication and inherited through mitosis. How this may sustain the epigenome and cell identity remains unknown. Here, we show that transmission of histone-based information during replication maintains epigenome fidelity and embryonic stem cell plasticity. Asymmetric segregation of parental histones H3-H4 in MCM2-2A mutants compromised mitotic inheritance of histone modifications and globally altered the epigenome. This included widespread spurious deposition of repressive modifications, suggesting elevated epigenetic noise. Moreover, H3K9me3 loss at repeats caused de-repression and H3K27me3 redistribution across bivalent promoters correlated with misexpression of developmental genes. MCM2-2A mutation challenged dynamic transitions in cellular states across the cell cycle, enhancing naïve pluripotency and reducing lineage priming in G1. Further, developmental competence was diminished, correlating with impaired exit from pluripotency. Collectively, this argues that epigenetic inheritance of histone modifications maintains a correctly balanced and dynamic chromatin landscape able to support mammalian differentiation.
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Project description:Modified parental histones are segregated symmetrically to daughter DNA strands during replication and inherited through mitosis. How this may sustain the epigenome and cell identity remains unknown. Here, we show that transmission of histone-based information during replication maintains epigenome fidelity and embryonic stem cell plasticity. Asymmetric segregation of parental histones H3-H4 in MCM2-2A mutants compromised mitotic inheritance of histone modifications and globally altered the epigenome. This included widespread spurious deposition of repressive modifications, suggesting elevated epigenetic noise. Moreover, H3K9me3 loss at repeats caused de-repression and H3K27me3 redistribution across bivalent promoters correlated with misexpression of developmental genes. MCM2-2A mutation challenged dynamic transitions in cellular states across the cell cycle, enhancing naïve pluripotency and reducing lineage priming in G1. Further, developmental competence was diminished, correlating with impaired exit from pluripotency. Collectively, this argues that epigenetic inheritance of histone modifications maintains a correctly balanced and dynamic chromatin landscape able to support mammalian differentiation.
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Project description:Modified parental histones are segregated symmetrically to daughter DNA strands during replication and inherited through mitosis. How this may sustain the epigenome and cell identity remains unknown. Here, we show that transmission of histone-based information during replication maintains epigenome fidelity and embryonic stem cell plasticity. Asymmetric segregation of parental histones H3-H4 in MCM2-2A mutants compromised mitotic inheritance of histone modifications and globally altered the epigenome. This included widespread spurious deposition of repressive modifications, suggesting elevated epigenetic noise. Moreover, H3K9me3 loss at repeats caused de-repression and H3K27me3 redistribution across bivalent promoters correlated with misexpression of developmental genes. MCM2-2A mutation challenged dynamic transitions in cellular states across the cell cycle, enhancing naïve pluripotency and reducing lineage priming in G1. Further, developmental competence was diminished, correlating with impaired exit from pluripotency. Collectively, this argues that epigenetic inheritance of histone modifications maintains a correctly balanced and dynamic chromatin landscape able to support mammalian differentiation.
2023-06-15 | GSE196039 | GEO
Project description:The epigenetic process safeguards cell identity during cell division through the inheritance of appropriate gene expression profiles. We demonstrated previously that parental nucleosomes are inherited by the same chromatin domains during DNA replication only in the case of repressed chromatin. We now show that this specificity is conveyed by NPM1, a histone H3/H4 chaperone. Proteomic analyses of late S-phase chromatin revealed NPM1 in association with both H3K27me3, an integral component of facultative heterochromatin and MCM2, an integral component of the DNA replication machinery; moreover NPM1 interacts directly with PRC2 and with MCM2. Given that NPM1 is essential, the inheritance of repressed chromatin domains was examined anew using mESCs expressing an auxin-degradable version of endogenous NPM1. Upon NPM1 degradation, cells accumulated in S-phase of the cell-cycle and parental nucleosome inheritance from repressed chromatin domains was markedly compromised. Appropriate inheritance required the NPM1 acidic patches that function in chaperone activity, pointing to NPM1 being integral to the epigenetic process.
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Project description:During DNA replication modified parental histones H3-H4 are segregated almost symmetrically to the two daughter DNA strands enabling mitotic inheritance of histone PTMs. Whether heritable histone modifications confer epigenetic regulation by maintaining chromatin states and gene expression is unclear. Using MCM2 histone-binding mutant embryonic stem cells (ESCs) and mass spectrometry, we show that asymmetric segregation of parental histones to the leading strand causes imbalanced inheritance of histone H3K27 methylations to daughter cells.
2023-08-30 | PXD020326 | Pride
Project description:The transgenerational inheritance of epigenetic information is an attractive mechanism by which the phenotypic consequences of exposure of parents to certain environmental conditions could be transmitted to the next generation. Although this phenomenon is well described in yeast and plants, and in some invertebrates, such as the D. melanogaster and C. elegans, the evidence for transgenerational inheritance in vertebrates is scarce. Among the mechanisms that are known or suspected to be involved in mediating the propagation of epigenetic information to subsequent generations, the process of enzymatic DNA methylation is of particular interest. During DNA replication, the methylation pattern of the parental strand is faithfully copied onto the daughter strand by the maintenance methylase DNMT1, although methylation patterns can be changed through the action of de novo methylases and mechanisms of active and passive demethylation. In the context of epigenetic inheritance, the induction of aberrant methylation patterns in gametes may set the stage for transmission into future generations. Here, we describe a viable hypomorphic allele of dnmt1 in zebrafish that causes widespread demethylation of CpG dinucleotides in sperm and somatic tissues. Surprisingly, homozygous mutants present with an essentially normal phenotype, with the exception of drastically impaired lymphopoiesis, affecting both larval and adult phases of T cell development. Male but not female mutants are fertile. The phenotype of impaired larval (but not adult) T cell development is transmitted to subsequent generations by about 50% of fish that are genotypically wildtype. Whole genome bisulfite sequencing of sperm DNA of transmitting and non-transmitting males identified about 200 differentially methylated regions, including hypermethylated sites associated with runx3 and rptor genes. Knock-down of these two genes leads to impaired larval T cell development. Our results raise the possibility of an epigenetic origin of certain immunodeficiency syndromes in animals and humans.
2020-07-07 | GSE98647 | GEO
Project description:To understand whether parental histone PTM landscape plays roles in cell differentiation, we perturbed parental histone PTM allocation by mutating histone chaperone MCM2 on its histone binding domain (MCM2-2A mutation), disrupted only the histone transferring of MCM2 protein in mouse embryonic stem cells (ESCs). Combining single-cell transcriptomics and epigenomics with lineage barcoding, we found that MCM2-2A mutant ESCs cannot be fully differentiated to neuronal precursor cells (NPCs), causing by the redistribution of H3K27me3, and subsequently NPC related gene expression. Here, we show that the parental histone allocation plays an important role in the establishment of chromatin landscapes, altering ESC differentiational potential, shaping expression programs and cell heterogeneity.
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