Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Progressive methylation of ageing histones by Dot1 functions as a timer.

ABSTRACT: Post-translational modifications of histone proteins have a crucial role in regulating gene expression. If efficiently re-established after chromosome duplication, histone modifications could help propagate gene expression patterns in dividing cells by epigenetic mechanisms. We used an integrated approach to investigate the dynamics of the conserved methylation of histone H3 Lys 79 (H3K79) by Dot1. Our results show that methylation of H3K79 progressively changes after histone deposition, which is incompatible with a rapid copy mechanism. Instead, methylation accumulates on ageing histones, providing the cell with a timer mechanism to directly couple cell-cycle length to changes in chromatin modification on the nucleosome core.

SUBMITTER: De Vos D

PROVIDER: S-EPMC3166457 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Progressive methylation of ageing histones by Dot1 functions as a timer.

De Vos Dirk D Frederiks Floor F Terweij Marit M van Welsem Tibor T Verzijlbergen Kitty F KF Iachina Ekaterina E de Graaf Erik L EL Altelaar A F Maarten AF Oudgenoeg Gideon G Heck Albert J R AJ Krijgsveld Jeroen J Bakker Barbara M BM van Leeuwen Fred F

EMBO reports 20110901 9

Post-translational modifications of histone proteins have a crucial role in regulating gene expression. If efficiently re-established after chromosome duplication, histone modifications could help propagate gene expression patterns in dividing cells by epigenetic mechanisms. We used an integrated approach to investigate the dynamics of the conserved methylation of histone H3 Lys 79 (H3K79) by Dot1. Our results show that methylation of H3K79 progressively changes after histone deposition, which i ...[more]

PMID: 21760613

Similar Datasets

The diverse functions of Dot1 and H3K79 methylation.

Project description:DOT1 (disruptor of telomeric silencing; also called Kmt4) was initially discovered in budding yeast in a genetic screen for genes whose deletion confers defects in telomeric silencing. Since the discovery ?10 years ago that Dot1 and its mammalian homolog, DOT1L (DOT1-Like), possess histone methyltransferase activity toward histone H3 Lys 79, great progress has been made in characterizing their enzymatic activities and the role of Dot1/DOT1L-mediated H3K79 methylation in transcriptional regulation, cell cycle regulation, and the DNA damage response. In addition, gene disruption in mice has revealed that mouse DOT1L plays an essential role in embryonic development, hematopoiesis, cardiac function, and the development of leukemia. The involvement of DOT1L enzymatic activity in leukemogenesis driven by a subset of MLL (mixed-lineage leukemia) fusion proteins raises the possibility of targeting DOT1L for therapeutic intervention.

| S-EPMC3134078 | biostudies-literature

Dot1 and histone H3K79 methylation in natural telomeric and HM silencing.

Project description:The expression of genes residing near telomeres is attenuated through telomere position-effect variegation (TPEV). By using a URA3 reporter located at TEL-VII-L of Saccharomyces cerevisiae, it was proposed that the disruptor of telomeric silencing-1 (Dot1) regulates TPEV by catalyzing H3K79 methylation. URA3 reporter assays also indicated that H3K79 methylation is required for HM silencing. Surprisingly, a genome-wide expression analysis of H3K79 methylation-defective mutants identified only a few telomeric genes, such as COS12 at TEL-VII-L, to be subject to H3K79 methylation-dependent natural silencing. Consistently, loss of Dot1 did not globally alter Sir2 or Sir3 occupancy in subtelomeric regions, but only led to some telomere-specific changes. Furthermore, H3K79 methylation by Dot1 did not play a role in the maintenance of natural HML silencing. Therefore, commonly used URA3 reporter assays may not report on natural PEV, and therefore, studies concerning the epigenetic mechanism of silencing in yeast should also employ assays reporting on natural gene expression patterns.

| S-EPMC3085244 | biostudies-literature

Dot1 binding induces chromatin rearrangements by histone methylation-dependent and -independent mechanisms.

Project description:BACKGROUND: Methylation of histone H3 lysine 79 (H3K79) by Dot1 is highly conserved among species and has been associated with both gene repression and activation. To eliminate indirect effects and examine the direct consequences of Dot1 binding and H3K79 methylation, we investigated the effects of targeting Dot1 to different positions in the yeast genome. RESULTS: Targeting Dot1 did not activate transcription at a euchromatic locus. However, chromatin-bound Dot1 derepressed heterochromatin-mediated gene silencing over a considerable distance. Unexpectedly, Dot1-mediated derepression was established by both a H3K79 methylation-dependent and a methylation-independent mechanism; the latter required the histone acetyltransferase Gcn5. By monitoring the localization of a fluorescently tagged telomere in living cells, we found that the targeting of Dot1, but not its methylation activity, led to the release of a telomere from the repressive environment at the nuclear periphery. This probably contributes to the activity-independent derepression effect of Dot1. CONCLUSIONS: Targeting of Dot1 promoted gene expression by antagonizing gene repression through both histone methylation and chromatin relocalization. Our findings show that binding of Dot1 to chromatin can positively affect local gene expression by chromatin rearrangements over a considerable distance.

| S-EPMC3038881 | biostudies-other

Nucleocytoplasmic shuttling of a GATA transcription factor functions as a development timer.

Project description:Biological oscillations are observed at many levels of cellular organization. In the social amoeba Dictyostelium discoideum, starvation-triggered multicellular development is organized by periodic cyclic adenosine 3',5'-monophosphate (cAMP) waves, which provide both chemoattractant gradients and developmental signals. We report that GtaC, a GATA transcription factor, exhibits rapid nucleocytoplasmic shuttling in response to cAMP waves. This behavior requires coordinated action of a nuclear localization signal and reversible G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor-mediated phosphorylation. Although both are required for developmental gene expression, receptor occupancy promotes nuclear exit of GtaC, which leads to a transient burst of transcription at each cAMP cycle. We demonstrate that this biological circuit filters out high-frequency signals and counts those admitted, thereby enabling cells to modulate gene expression according to the dynamic pattern of the external stimuli.

| S-EPMC4061987 | biostudies-literature

Nucleocytoplasmic shuttling of a GATA transcription factor functions as a development timer

Project description:Biological oscillations are observed at many levels of cellular organization. In the social amoebae Dictyostelium discoideum, starvation-triggered multicellular development is organized by periodic cAMP waves, which provide both chemoattractant gradients and developmental signals. We report that GtaC, a GATA transcription factor, exhibits rapid nucleocytoplasmic shuttling in response to cAMP waves. This behavior requires coordinated action of a nuclear localization signal and reversible G protein-coupled receptor (GPCR)-mediated phosphorylation. While both are required for developmental gene expression, receptor occupancy promotes nuclear exit of GtaC, which leads to a transient burst of transcription at each cAMP cycle. We demonstrate that this biological circuit, like an M-bM-^@M-^\edge triggerM-bM-^@M-^], filters out high frequency signals and counts those admitted, thereby enabling cells to modulate gene expression according to the dynamic pattern of the external stimuli. Transcriptional profiling during early development of wild-type, gtaC, GFP-GtaC/gtaC, and NLSex-GFP-GtaC/gtaC strains

2014-04-15 | E-GEOD-54866 | biostudies-arrayexpress

Two DOT1 enzymes cooperatively mediate efficient ubiquitin-independent histone H3 lysine 76 tri-methylation in kinetoplastids.

Project description:In higher eukaryotes, a single DOT1 histone H3 lysine 79 (H3K79) methyltransferase processively produces H3K79me2/me3 through histone H2B mono-ubiquitin interaction, while the kinetoplastid Trypanosoma brucei di-methyltransferase DOT1A and tri-methyltransferase DOT1B efficiently methylate the homologous H3K76 without H2B mono-ubiquitination. Based on structural and biochemical analyses of DOT1A, we identify key residues in the methyltransferase motifs VI and X for efficient ubiquitin-independent H3K76 methylation in kinetoplastids. Substitution of a basic to an acidic residue within motif VI (Gx6K) is essential to stabilize the DOT1A enzyme-substrate complex, while substitution of the motif X sequence VYGE by CAKS renders a rigid active-site loop flexible, implying a distinct mechanism of substrate recognition. We further reveal distinct methylation kinetics and substrate preferences of DOT1A (H3K76me0) and DOT1B (DOT1A products H3K76me1/me2) in vitro, determined by a Ser and Ala residue within motif IV, respectively, enabling DOT1A and DOT1B to mediate efficient H3K76 tri-methylation non-processively but cooperatively, and suggesting why kinetoplastids have evolved two DOT1 enzymes.

| S-EPMC10951340 | biostudies-literature

The Apaf-1*procaspase-9 apoptosome complex functions as a proteolytic-based molecular timer.

Project description:During stress-induced apoptosis, the initiator caspase-9 is activated by the Apaf-1 apoptosome and must remain bound to retain significant catalytic activity. Nevertheless, in apoptotic cells the vast majority of processed caspase-9 is paradoxically observed outside the complex. We show herein that apoptosome-mediated cleavage of procaspase-9 occurs exclusively through a CARD-displacement mechanism, so that unlike the effector procaspase-3, procaspase-9 cannot be processed by the apoptosome as a typical substrate. Indeed, procaspase-9 possessed higher affinity for the apoptosome and could displace the processed caspase-9 from the complex, thereby facilitating a continuous cycle of procaspase-9 recruitment/activation, processing, and release from the complex. Owing to its rapid autocatalytic cleavage, however, procaspase-9 per se contributed little to the activation of procaspase-3. Thus, the Apaf-1 apoptosome functions as a proteolytic-based 'molecular timer', wherein the intracellular concentration of procaspase-9 sets the overall duration of the timer, procaspase-9 autoprocessing activates the timer, and the rate at which the processed caspase-9 dissociates from the complex (and thus loses its capacity to activate procaspase-3) dictates how fast the timer 'ticks' over.

| S-EPMC2711187 | biostudies-other

The methylation landscape of giga-genome and the epigenetic timer of age in Chinese pine.

Project description:Epigenetics has been revealed to play a crucial role in the long-term memory in plants. However, little is known about whether the epigenetic modifications occur with age progressively in conifers. Here, we present the single-base resolution DNA methylation landscapes of the 25-gigabase Chinese pine (Pinus tabuliformis) genome at different ages. The result shows that DNA methylation is closely coupled with the regulation of gene transcription. The age-dependent methylation profile with a linearly increasing trend is the most significant pattern of DMRs between ages. Two segments at the five-prime end of the first ultra-long intron in DAL1, a conservative age biomarker in conifers, shows a gradual decline of CHG methylation as the age increased, which is highly correlated with its expression profile. Similar high correlation is also observed in nine other age marker genes. Our results suggest that DNA methylation serves as an important epigenetic signature of developmental age in conifers.

| S-EPMC10082083 | biostudies-literature

Dot1-dependent histone H3K79 methylation promotes the formation of meiotic double-strand breaks in the absence of histone H3K4 methylation in budding yeast.

Project description:Epigenetic marks such as histone modifications play roles in various chromosome dynamics in mitosis and meiosis. Methylation of histones H3 at positions K4 and K79 is involved in the initiation of recombination and the recombination checkpoint, respectively, during meiosis in the budding yeast. Set1 promotes H3K4 methylation while Dot1 promotes H3K79 methylation. In this study, we carried out detailed analyses of meiosis in mutants of the SET1 and DOT1 genes as well as methylation-defective mutants of histone H3. We confirmed the role of Set1-dependent H3K4 methylation in the formation of double-strand breaks (DSBs) in meiosis for the initiation of meiotic recombination, and we showed the involvement of Dot1 (H3K79 methylation) in DSB formation in the absence of Set1-dependent H3K4 methylation. In addition, we showed that the histone H3K4 methylation-defective mutants are defective in SC elongation, although they seem to have moderate reduction of DSBs. This suggests that high levels of DSBs mediated by histone H3K4 methylation promote SC elongation.

| S-EPMC4010517 | biostudies-literature

Progressive Senescence Programs Elicit Intrinsic Vulnerability to Ageing-related Cancer

Project description:Cancer incidence escalates exponentially with advancing age, the mechanism of which remains obscure. Here we built up a chronological molecular clock at the single cell level for the mammary stem cell enriched population to depict the physiological ageing dynamics. We found the mammary ageing process was asynchronous and progressive, determined by the relative proportions of four distinct cellular states. The mammary ageing was initiated by a light senescence state with elevated NFkb, P53 signals, followed by a deep senescence state with reduced NFkb, P53 and enhanced PI3K-Akt-mTOR, Wnt, Notch and pluripotency activities succumb to cancer predisposition. Both of these senescence programs were regulated by a master mammary stem cell factor Bcl11b through modulation of multiple stress, longevity and pluripotency associated pathways. Depletion of Bcl11b triggered morphological, functional and molecular ageing-like phenotypes, and drastically enhanced DMBA-induced tumor formation. We further screened out a drug TPCA-1 that can elevate Bcl11b activity, rejuvenate mammary cells transcriptomically and significantly reduce the ageing-related cancer incidence. Our findings established a molecular portrait of progressive mammary cell ageing and elucidated the regulatory network bridging mammary ageing and cancer predisposition that can be modulated to control the cancer initiation, which has potential implications in management of cancer prevalence.

2024-04-02 | GSE195647 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data