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Domain model explain propagation dynamics and stability of K27 and K36 methylation landscapes

ABSTRACT: Chromatin states must be stably maintained during cell proliferation to uphold cellular identity and genome integrity. Inheritance of histone modifications across cell division is thought to be central in this process. However, the histone modification landscape is challenged by the incorporation new unmodified histones during each cell cycle and the principles that govern heritability remain poorly defined. Here, we take a quantitative approach and develop a reusable computational model that describes propagation of K27 and K36 methylation states. We measure combinatorial K27 and K36 methylation patterns by quantitative mass spectrometry on subsequent generations of histones in the presence and absence of enzymatic inhibition. Our modelling rejects active global demethylation and invoke the existence of 8 domains defined by distinct methylation endpoints. We find that K27me3 on pre-existing histones stimulates the rate of de novo K27me3 establishment, supporting a read-write mechanism in timely chromatin restoration. Finally, we provide a detailed, quantitative picture of the mutual antagonism between K27 and K37 methylation, and propose that this antagonism enhance the stability of epigenetic states across cell division.

OTHER RELATED OMICS DATASETS IN: PXD014807

ORGANISM(S): Mus musculus

PROVIDER: GSE135029 | GEO | 2020/04/08

REPOSITORIES: GEO

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Domain model explains propagation dynamics and stability of K27 and K36 methylation landscape

Project description:Chromatin states must be stably maintained during cell proliferation to uphold cellular identity and genome integrity. Inheritance of histone modifications across cell division is thought to be central in this process. However, the histone modification landscape is challenged by the incorporation of new unmodified histones during each cell cycle and the principles that govern heritability remain poorly defined. Here, we take a quantitative approach and develop a reusable computational model that describes propagation of K27 and K36 methylation states. We measure combinatorial K27 and K36 methylation patterns by quantitative mass spectrometry on subsequent generations of histones in the presence and absence of enzymatic inhibition. Our modelling rejects active global demethylation and invoke the existence of 8 domains defined by distinct methylation endpoints. We find that K27me3 on pre- existing histones stimulates the rate of de novo K27me3 establishment, supporting a read-write mechanism in timely chromatin restoration. Finally, we provide a detailed, quantitative picture of the mutual antagonism between K27 and K37 methylation, and propose that this antagonism enhance the stability of epigenetic states across cell division.

2020-01-29 | PXD014807 | Pride

Domain model explain propagation dynamics and stability of K27 and K36 methylation landscapes

Project description:Domain model explain propagation dynamics and stability of K27 and K36 methylation landscapes

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Histone H3 K36 trimethylation in wild-type BY4741 yeast strains

Project description:ChIP-on chip assays to measure the change in histone H3 K36 trimethylation over the yeast genome in wild-type yeast strains.

2012-07-25 | GSE37105 | GEO

Histone H3 K36 trimethylation in wild-type BY4741 yeast strains

Project description:ChIP-on chip assays to measure the change in histone H3 K36 trimethylation over the yeast genome in wild-type yeast strains. Two color experiment.WT cells. Biological replicates=3 per IP per cell type.

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Histone H3.3 G34 mutations alter histone H3K36 and H3K27 methylation in cis

Project description:High-throughput sequencing of numerous patient samples has identified a myriad of frequent mutations of epigenetic regulators in human cancers, including recently discovered mutations in histone-encoding genes. Lysine-to-methionine mutations such as H3K27M and H3K36M share a common mechanism of inhibiting methylation pathways at the genome-wide level to promote tumorigenesis. However, the mechanism underlying the molecular and cellular changes due to H3G34 alterations is yet to be determined. H3G34 itself is not post-translationally modified; however, G34 lies in close proximity to K36, which undergoes methylation during transcriptional elongation. In Hela cells, H3.3G34L/W mutations have no effect on global levels of methylation on H3K36, H3K27, or other major methylation sites on endogenous histone H3, which include both H3.3 and the canonical H3.1/H3.2 proteins. However, long exposures of the blots revealed that methylation on the ectopic Flag-H3.3 proteins are affected by G34 mutations: with di- and trimethylation on H3K36 and H3K27ac reduced whereas H3K27me3 increased in the G34L and G34W mutated H3.3 compared to the WT H3.3. ChIP-seq results showed that mutations of H3.3G34 affect methylation on H3K36 and H3K27 in cis. G34L/W mutants abolish SETD2 methylation of H3K36. In contrast, the enzymatic activities of both EZH2 and p300 on H3K27 are not affected by G34 mutations. Consistent with changes in H3K27me3 and H3K36m3 levels, we found increased binding of PRC2 (EZH2, SUZ12 and EED) and PRC1 complex components (CBX8 and RING2) and reduced binding of H3.3K36me3 reader such as ZMYND11 to the G34 mutants. In summary, our study revealed that histone H3.3 G34 mutations alter histone K36 and K27 methylation in cis, and affect the binding of readers specific to K36 or K27 methylation.

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Two distinct modes for propagation of histone PTMs across the cell cycle

Project description:Epigenetic states defined by chromatin can be maintained through mitotic cell division. However, it remains unknown how histone-based information is transmitted. Here we combine nascent chromatin capture (NCC) and triple-SILAC labelling to track histone modifications and histone variants during DNA replication and across the cell cycle. We show that post-translational modifications (PTMs) are transmitted with parental histones to newly replicated DNA. Di- and tri-methylation marks are diluted two-fold upon DNA replication, as a consequence of new histone deposition. Importantly, within one cell cycle all PTMs are restored. In general, new histones are modified to mirror the parental histones. However, H3K9me3 and H3K27me3 are propagated by continuous modification of parental and new histones, because the establishment of these marks extends over several cell generations. Together, our results reveal how histone marks propagate and demonstrate that chromatin states oscillate within the cell cycle.

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Combined double knockout of Ezh2 and G9a leads to expression change in murine retinal ganglion cells

Project description:Purpose: The goal of this study is to evaluate H3K27me3 histone marks in retinal ganglion cells in Ezh2 (Math5Cre, Ezh2-/-) and combined G9a-Ezh2 (Math5Cre; G9a+/-Ezh2-/-) knockout mutant mice at P1. Both Ezh2 and G9a are major epigenetic silencing machineries. Ezh2 mediates the trimethylation of lysine 27 on histone 3. Emerging evidences show an interdependence between Ezh2 and G9a to facilitate K27 trimethylation. Methods: P1 retinal ganglion cells were collected and chromatin immunoprecipitation was performed with EZ- CHIP kit from Millipore. Library preparation was done with Rubicon Genomics Thruplex DNAseq. Results: Here, we find a pool of common K27me3 target genes of Ezh2 and G9a in double knockout that leads to dysfunction in double mutant RGCs. Conclusion: This study provides the first Chip-seq analysis of K27me3 in murine RGCs. Our data supports that an interaction between Ezh2 and G9a is also evident in murine retinal ganglion cells. This work should be a framework for further study of retinal ganglion cells and retinal diseases.

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Inactivation of the histone H3 K36 methyltransferase NSD1 confers resistance to EZH2 inhibition [ChIP-Seq]

Project description:Disruption of antagonism between SWI/SNF chromatin remodelers and Polycomb repressor complexes drives the formation of numerous cancer types. Recently, an inhibitor of Polycomb protein EZH2 was approved for treatment of sarcomas mutant in SWI/SNF subunit SMARCB1, but resistance occurs. Here we sought to identify additional contributors to SWI/SNF-Polycomb antagonism and potential resistance mechanisms. We performed CRISPR screens and found that NSD1 loss caused resistance to EZH2 inhibition. NSD1 loss reduced H3K36me2 and impaired transcriptional activation of targets inhibited by EZH2 or activated by SMARCB1. Further, inhibiting the H3K36me2 demethylase KDM2A restored EZH2 inhibition in cells lacking NSD1. Our results expand the mechanistic understanding of SWI/SNF and Polycomb interplay and identify NSD1 as key for coordinating this transcriptional control.

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Inactivation of the histone H3 K36 methyltransferase NSD1 confers resistance to EZH2 inhibition [RNA-Seq]

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