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H3K79 methylation - cell cycle

ABSTRACT: Mammalian DNA replication starts at distinct chromosomal sites in a tissue-specific pattern coordinated with transcription, but previous studies have not yet identified a chromatin modification that correlates with the initiation of DNA replication. This submission is associated with a paper in which we report that replication initiation events are associated with a high frequency of methylation of histone H3 on lysine K79 (H3K79Me2 and H3K79Me3). H3K79Me2-containing chromatin exhibited the highest enrichment of replication initiation events observed in a single chromatin modification. Importantly, H3K79 methylation was enriched in chromatin containing a replicator (a DNA sequence capable of initiating DNA replication), but not in chromatin containing a mutant replicator that could not initiate replication. The association of H3K79Me2 with replication initiation sites was independent and not synergistic with other chromatin modifications. H3K79 methylation exhibited a wider distribution and greater abundance during S-phase, but regions of chromatin that were only modified during S-phase were not enriched in replication initiation events. In addition, the paper shows that depletion of DOT1L, the sole enzyme responsible for H3K79 methylation, triggered limited genomic over-replication. These data are consistent with the hypothesis that methylation of H3K79 associates with replication origins and marks replicated chromatin during S-phase to prevent re-replication and preserve genomic stability.

ORGANISM(S): Homo sapiens

PROVIDER: GSE35294 | GEO | 2013/06/06

SECONDARY ACCESSION(S): PRJNA151597

REPOSITORIES: GEO

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H3K79 methylation - cell cycle

Project description:Mammalian DNA replication starts at distinct chromosomal sites in a tissue-specific pattern coordinated with transcription, but previous studies have not yet identified a chromatin modification that correlates with the initiation of DNA replication. This submission is associated with a paper in which we report that replication initiation events are associated with a high frequency of methylation of histone H3 on lysine K79 (H3K79Me2 and H3K79Me3). H3K79Me2-containing chromatin exhibited the highest enrichment of replication initiation events observed in a single chromatin modification. Importantly, H3K79 methylation was enriched in chromatin containing a replicator (a DNA sequence capable of initiating DNA replication), but not in chromatin containing a mutant replicator that could not initiate replication. The association of H3K79Me2 with replication initiation sites was independent and not synergistic with other chromatin modifications. H3K79 methylation exhibited a wider distribution and greater abundance during S-phase, but regions of chromatin that were only modified during S-phase were not enriched in replication initiation events. In addition, the paper shows that depletion of DOT1L, the sole enzyme responsible for H3K79 methylation, triggered limited genomic over-replication. These data are consistent with the hypothesis that methylation of H3K79 associates with replication origins and marks replicated chromatin during S-phase to prevent re-replication and preserve genomic stability. Evaluation of HeK79 methylation in chromatin samples from cell cycle fractionated K562 leukemia cells. Unsyncrhonized untreated cultures of K562 cells were fractionated by size using centrifugal elutriation. Chromatin was isolated and subject to ChIP-Seq with antibodies directed against dimethylated and trimethylated lysine on histone H3.

2013-06-06 | E-GEOD-35294 | biostudies-arrayexpress

Chromatin immunoprecipitation in dot1 deletion and G1 or G2 arrested yeast cells to identify methylation patterns

Project description:To define the molecular regulators required for differential pattern of H3K79 methylation by Dot1, we performed a GPS screen and discovered that the components of the cell cycle-regulated SBF complex were required for normal levels of H3K79 di- but not trimethylation. Genome-wide mapping revealed that H3K79 di- and trimethylation to present a mutually exclusive pattern on chromatin with M/G1 cell-cycle-regulated genes significantly enriched for H3K79 dimethylation. Since H3K79 trimethylation requires prior monoubiquitination of H2B, we performed genome-wide profiling of H2BK123 monoubiquitination and showed that H2BK123 monoubiquitination is excluded from cell cycle regulated genes and sites containing H3K79me2 but not from H3K79me3 containing regions. A genome-wide screen for factors responsible for the establishment/removal of H3K79 dimethylation resulted in the identification of several genes including NRM1 and WHI3, which both impact the transcription by the SBF, and MBF complexes, further linking the regulation of H3K79's methylation status to the cell cycle.

2009-10-19 | E-MEXP-2273 | biostudies-arrayexpress

Menin is a ‘reader’ of histone H3 lysine 79 methylation (RNA-Seq)

Project description:Methylation of histone H3 lysine-79 is an epigenetic mark for gene regulation in development, cellular differentiation and disease progression. However, it remains poorly understood how this histone mark is translated into downstream effects due to the lack of knowledge of H3K79 methylation ‘readers’. Here, we develop a nucleosome-based photoaffinity probe to capture proteins that recognize H3K79 dimethylation (H3K79me2) in nucleosomal context. In combination with a quantitative proteomics approach, this probe identifies menin as a bona fide “reader” for H3K79me2. Menin directly and selectively binds to the nucleosome with H3K79me2 mark in vitro. In cells, menin is tightly associated with this histone mark on chromatin, particularly in gene bodies. Reading H3K79me2 at intragenic enhancers, menin promotes gene transcription, likely by mediating enhancer–promoter interactions.

2023-02-17 | GSE202592 | GEO

Menin is a ‘reader’ of histone H3 lysine 79 methylation (ChIP-Seq)

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Global gene expression analysis of Dot1l-deficient and control intestinal villus cells in mouse

Project description:Methylation of H3K79 is associated with chromatin at expressed genes, though it is unclear if this histone modification is required for transcription of all genes. Recent studies suggest that Wnt-responsive genes depend particularly on H3K79 methylation, which is catalyzed by the methyltransferase DOT1L. Human leukemias carrying MLL gene rearrangements show DOT1L-mediated H3K79 methylation and aberrant expression of leukemogenic genes. DOT1L inhibitors reverse these effects but their clinical use is potentially limited by toxicity in Wnt-dependent tissues such as intestinal epithelium. Genome-wide positioning of the H3K79me2 mark in Lgr5+ mouse intestinal stem cells and mature intestinal villus epithelium correlated with mRNA expression levels but not with Wnt-responsive genes per se. Selective Dot1l disruption in Lgr5+ stem cells or in all intestinal epithelial cells eliminated H3K79me2 from the respective compartments, allowing genetic evaluation of DOT1L requirements. Absence of methylated H3K79 did not impair health, intestinal homeostasis or expression of Wnt target genes in crypt epithelium for up to 4 months, despite increased crypt cell apoptosis. Global transcript profiles in Dot1l-null cells were barely altered. Thus, H3K79 methylation is not essential for transcription of Wnt-responsive or other intestinal genes and intestinal toxicity is not imperative when DOT1L is rendered inactive in vivo. Examination of differential gene expression between Dot1l control (Dot1 f/f) and Dot1l mutant (Villin-Cre, Dot1l f/f) villus cells.

2012-10-19 | E-GEOD-41710 | biostudies-arrayexpress

Global gene expression analysis of Dot1l-deficient and control intestinal villus cells in mouse

2012-10-19 | GSE41710 | GEO

DOT1L Inhibits SIRT1 and SUV39H1-Mediated H3K9 Modification to Maintain Gene Expression (ATACseq)

Project description:Methylation of histone 3 on lysine 79 (H3K79) is broadly associated with active gene expression in eukaryotes, and the H3K79 methyltransferase DOT1L is indispensable for specific leukemia subtypes like those with MLL-translocations. We found that suppression of the histone deacetylase SIRT1 rescued MLL-AF9 leukemia cells from their dependence on DOT1L. We show that upon DOT1L inhibition, SIRT1 is required for the acquisition of a repressive chromatin state consistent with facultative heterochromatin around MLL-AF9 target genes in leukemia and other genes possess an H3K79me2(hi), H3K9ac(hi), H3K9me2(low) histone modification profile in normal hematopoietic stem and progenitor cells. Examination of histone modifications and a chromatin modifier with and without drug treatment and RNA interference.

2015-03-30 | E-GEOD-61016 | biostudies-arrayexpress

DOT1L Inhibits SIRT1 and SUV39H1-Mediated H3K9 Modification to Maintain Gene Expression (ChIPseq)

2015-03-30 | E-GEOD-61021 | biostudies-arrayexpress

Epigenetic profiling of hematopoietic stem cells and leukemia stem cells

Project description:The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations that involve the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in a murine MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3 and H3K36me3. Histone methylation patterns are highly abnormal on MLL-AF9 fusion target loci, defining a distinct epigenetic lesion involving H3K79. Conditional inactivation of Dot1l leads to specific down-regulation of direct MLL-AF9 targets and an MLL-translocation associated gene expression signature, while global transcription levels remain largely unaffected. This correlated with a greater sensitivity of leukemic blasts towards loss of Dot1l compared to normal hematopoietic cells. Development of in vivo leukemia was absolutely dependent on Dot1l. Chromatin immunoprecipitation followed by Solexa sequencing for H3K4me3, H3K27me3, H3K36me3, H3K79me2 and biotinylated MLL-AF9 in HSC, GMP and LSC.

2011-09-13 | E-GEOD-29130 | biostudies-arrayexpress

ChIP-Seq of H3K79me2 in Mouse Embryonic Fibroblasts

Project description:H3K79 dimethylation is a mark of transcriptional elongation. To gain insight into the set of genes actively transcribed in MEFs, chromatin immunoprecipitation coupled with massive parallel sequencing (ChIP-seq) was performed to determine the presence of H3K79me2 across the genome. DNA was enriched by chromatin immunoprecipitation (ChIP) and analyzed by Solexa sequencing. ChIP was performed using an antibody against H3K79me2.

2010-06-15 | E-GEOD-22268 | biostudies-arrayexpress

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