Neuronal Dot1ll is a broad mitochondrial gene-repressor associated with human brain aging via H3K79 hypermethylation
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ABSTRACT:
PROVIDER: PRJNA767004 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16097429.fastq.gz | Fastqsanger.gz | |||
| SRR16097430.fastq.gz | Fastqsanger.gz | |||
| SRR16097431.fastq.gz | Fastqsanger.gz | |||
| SRR16097432.fastq.gz | Fastqsanger.gz | |||
| SRR16097433.fastq.gz | Fastqsanger.gz |
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Project description:Neuronal Dot1ll is a broad mitochondrial gene-repressor associated with human brain aging via H3K79 hypermethylation II
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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
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.
2013-06-06 | GSE35294 | GEO
Project description:The methylation of histone H3 lysine 79 (H3K79) acts as an active chromatin marker and is enriched in actively transcribed regions of the genome. However, demethylase of this mark remains unknown despite intensive research. Here, we show that KDM2B (FBXL10), a member of the Jumonji C (JmjC) family of proteins and previously known for its histone H3K36 demethylase activity, is a di- and trimethyl H3K79 demethylase. We demonstrate that KDM2B induces transcriptional repression of HOXA7 and MEIS1 via occupancy of promoters and demethylation of H3K79. Furthermore, genome-wide analysis suggests that H3K79 methylation levels are increased when KDM2B is depleted, suggesting that KDM2B functions as an H3K79 demethylase in vivo. Finally, stable KDM2B-knockdown cell lines exhibited displacement of SIRT1, with concomitant increases in H3K79 methylation and H4K16 acetylation. Our findings identify KDM2B as an H3K79 demethylase and link its function to transcriptional repression via SIRT1-mediated chromatin silencing.
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Project description:Chromatin immunoprecipitation followed by Solexa sequencing for H3K27me3 and H3K79me2 in Fibroblasts, Embryonic stem cells, and fibroblast undergoing reprogramming Inhibition of the histone 3 lysine 79 (H3K79) methyltransferase increases repgoramming efficiency and genome-wide analysis of H3K79me2 distribution revealed that fibroblast-specific genes associated with the epithelial to mesenchymal transition lose H3K79me2 in the initial phases of reprogramming. Dot1L inhibition facilitates the loss of this mark from genes that are fated to be repressed in the pluripotent state.
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Project description:We created a mouse model where conditional expression of physiologic levels of an Mll-AF4 fusion oncogene induces development of acute lymphoblastic (ALL) or acute myeloid leukemias (AML). ChIP-chip analysis demonstrated increased histone H3 Lysine 79 (H3K79) dimethylation that correlated with Mll-AF4 associated gene expression profiles in murine ALLs, and in human MLL-rearranged leukemias. In addition, human MLL-rearranged ALLs can be distinguished from other ALLs by their genome-wide H3K79 methylation profiles. Keywords: Cell type comparison
2008-11-04 | GSE12362 | GEO
Project description:There is a growing realization that some aging-associated phenotypes/diseases have an epigenetic basis. Here we report the first genome-scale study of epigenomic dynamics during normal human aging. We identify aging-associated differentially methylated regions (aDMRs) in whole blood in a discovery cohort, and then replicate these aDMRs in sorted CD4+ T-cells and CD14+ monocytes in an independent cohort, suggesting that aDMRs occur in precursor haematopoietic cells. Further replication of the aDMRs in buccal cells, representing a tissue that originates from a different germ-layer compared with blood, demonstrates that the aDMR signature is a multi-tissue phenomenon. Moreover, we demonstrate that aging-associated DNA hypermethylation occurs predominantly at bivalent chromatin domain promoters. This same category of promoters, associated with key developmental genes, is frequently hypermethylated in cancers and in vitro cell culture, pointing to a novel mechanistic link between aberrant hypermethylation in cancer, aging, and cell culture. We measured the methylation state of 27,578 CpG sites (Illumina HumanMethylation27 array) in sorted human blood cells to validate aging-associated DMRs.
2010-06-24 | E-GEOD-20242 | biostudies-arrayexpress
Project description:There is a growing realization that some aging-associated phenotypes/diseases have an epigenetic basis. Here we report the first genome-scale study of epigenomic dynamics during normal human aging. We identify aging-associated differentially methylated regions (aDMRs) in whole blood in a discovery cohort, and then replicate these aDMRs in sorted CD4+ T-cells and CD14+ monocytes in an independent cohort, suggesting that aDMRs occur in precursor haematopoietic cells. Further replication of the aDMRs in buccal cells, representing a tissue that originates from a different germ-layer compared with blood, demonstrates that the aDMR signature is a multi-tissue phenomenon. Moreover, we demonstrate that aging-associated DNA hypermethylation occurs predominantly at bivalent chromatin domain promoters. This same category of promoters, associated with key developmental genes, is frequently hypermethylated in cancers and in vitro cell culture, pointing to a novel mechanistic link between aberrant hypermethylation in cancer, aging, and cell culture. We measured the methylation state of 27,578 CpG sites (Illumina HumanMethylation27 array) in whole blood samples from 93 heathy human females aged between 49 and 74, to discover sites which change methylation state with age.
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