Survival in quiescence requires the euchromatic deployment of Clr4/SUV39H by Argonaute-associated small RNAs
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ABSTRACT:
ORGANISM(S): Schizosaccharomyces pombe
PROVIDER: GSE89151 | GEO | 2016/12/05
SECONDARY ACCESSION(S): PRJNA350496
REPOSITORIES: GEO
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Project description:Quiescence (G0) is a ubiquitous stress response through which cells enter reversible dormancy, acquiring distinct properties including reduced metabolism, resistance to stress, and long life. G0 entry involves dramatic changes to chromatin and transcription of cells, but the mechanisms coordinating these processes remain poorly understood. Using the fission yeast, here, we track G0-associated chromatin and transcriptional changes temporally and show that as cells enter G0, their survival and global gene expression programs become increasingly dependent on Clr4/SUV39H, the sole histone H3 lysine 9 (H3K9) methyltransferase, and RNAi proteins. Notably, G0 entry results in RNAi-dependent H3K9 methylation of several euchromatic pockets, prior to which Argonaute1-associated small RNAs from these regions emerge. Overall, our data reveal another function for constitutive heterochromatin proteins (the establishment of the global G0 transcriptional program) and suggest that stress-induced alterations in Argonaute-associated sRNAs can target the deployment of transcriptional regulatory proteins to specific sequences.
| S-EPMC5180613 | biostudies-literature
Project description:Cellular quiescence (G0) is a ubiquitous stress response through which cells enter a state of reversible dormancy, acquiring distinct properties including reduced metabolism, resistance to stress and long life. G0 entry involves dramatic changes to the chromatin landscape and transcriptional program of cells, but the mechanisms coordinating these processes remain poorly understood. Using the fission yeast, here we track the G0-associated chromatin and transcriptional changes temporally. We show that as cells enter G0, their survival and global gene expression programs become increasingly dependent on Clr4/SUV39H, the sole histone H3 lysine 9 (H3K9) methyltransferase, and RNA interference (RNAi) proteins. Notably, G0 entry results in RNAi-dependent H3K9 methylation of several euchromatic regions, prior to which Argonaute 1-associated small RNAs from these regions emerge. Overall our data reveal a new function for constitutive heterochromatin proteins in establishing the global G0 transcriptional program and suggest that stress-induced alterations in Argonaute-associated sRNAs can specify the deployment of transcriptional regulatory proteins to unique sites in eukaryotic genomes.
2016-12-05 | GSE89150 | GEO
Project description:Cellular quiescence (G0) is a ubiquitous stress response through which cells enter a state of reversible dormancy, acquiring distinct properties including reduced metabolism, resistance to stress and long life. G0 entry involves dramatic changes to the chromatin landscape and transcriptional program of cells, but the mechanisms coordinating these processes remain poorly understood. Using the fission yeast, here we track the G0-associated chromatin and transcriptional changes temporally. We show that as cells enter G0, their survival and global gene expression programs become increasingly dependent on Clr4/SUV39H, the sole histone H3 lysine 9 (H3K9) methyltransferase, and RNA interference (RNAi) proteins. Notably, G0 entry results in RNAi-dependent H3K9 methylation of several euchromatic regions, prior to which Argonaute 1-associated small RNAs from these regions emerge. Overall our data reveal a new function for constitutive heterochromatin proteins in establishing the global G0 transcriptional program and suggest that stress-induced alterations in Argonaute-associated sRNAs can specify the deployment of transcriptional regulatory proteins to unique sites in eukaryotic genomes.
2016-12-05 | GSE89149 | GEO
Project description:Cellular quiescence (G0) is a ubiquitous stress response through which cells enter a state of reversible dormancy, acquiring distinct properties including reduced metabolism, resistance to stress and long life. G0 entry involves dramatic changes to the chromatin landscape and transcriptional program of cells, but the mechanisms coordinating these processes remain poorly understood. Using the fission yeast, here we track the G0-associated chromatin and transcriptional changes temporally. We show that as cells enter G0, their survival and global gene expression programs become increasingly dependent on Clr4/SUV39H, the sole histone H3 lysine 9 (H3K9) methyltransferase, and RNA interference (RNAi) proteins. Notably, G0 entry results in RNAi-dependent H3K9 methylation of several euchromatic regions, prior to which Argonaute 1-associated small RNAs from these regions emerge. Overall our data reveal a new function for constitutive heterochromatin proteins in establishing the global G0 transcriptional program and suggest that stress-induced alterations in Argonaute-associated sRNAs can specify the deployment of transcriptional regulatory proteins to unique sites in eukaryotic genomes.
2016-12-05 | GSE89145 | GEO
Project description:Cellular quiescence (G0) is a ubiquitous stress response through which cells enter a state of reversible dormancy, acquiring distinct properties including reduced metabolism, resistance to stress and long life. G0 entry involves dramatic changes to the chromatin landscape and transcriptional program of cells, but the mechanisms coordinating these processes remain poorly understood. Using the fission yeast, here we track the G0-associated chromatin and transcriptional changes temporally. We show that as cells enter G0, their survival and global gene expression programs become increasingly dependent on Clr4/SUV39H, the sole histone H3 lysine 9 (H3K9) methyltransferase, and RNA interference (RNAi) proteins. Notably, G0 entry results in RNAi-dependent H3K9 methylation of several euchromatic regions, prior to which Argonaute 1-associated small RNAs from these regions emerge. Overall our data reveal a new function for constitutive heterochromatin proteins in establishing the global G0 transcriptional program and suggest that stress-induced alterations in Argonaute-associated sRNAs can specify the deployment of transcriptional regulatory proteins to unique sites in eukaryotic genomes.
2016-12-05 | GSE89142 | GEO
Project description:Survival in quiescence requires the euchromatic deployment of Clr4/SUV39H by Argonaute-associated small RNAs
| PRJNA350496 | ENA
Project description:Histone H3 lysine 9 methylation (H3K9me) mediates heterochromatic gene silencing and is important for genome stability and the regulation of gene expression1-4. The establishment and epigenetic maintenance of heterochromatin involve the recruitment of H3K9 methyltransferases to specific sites on DNA, followed by the recognition of pre-existing H3K9me by the methyltransferase and methylation of proximal histone H35-11. This positive feedback loop must be tightly regulated to prevent deleterious epigenetic gene silencing. Extrinsic anti-silencing mechanisms involving histone demethylation or boundary elements help to limit the spread of inappropriate H3K9me12-15. However, how H3K9 methyltransferase activity is locally restricted or prevented from initiating random H3K9me-which would lead to aberrant gene silencing and epigenetic instability-is not fully understood. Here we reveal an autoinhibited conformation in the conserved H3K9 methyltransferase Clr4 (also known as Suv39h) of the fission yeast Schizosaccharomyces pombe that has a critical role in preventing aberrant heterochromatin formation. Biochemical and X-ray crystallographic data show that an internal loop in Clr4 inhibits the catalytic activity of this enzyme by blocking the histone H3K9 substrate-binding pocket, and that automethylation of specific lysines in this loop promotes a conformational switch that enhances the H3K9me activity of Clr4. Mutations that are predicted to disrupt this regulation lead to aberrant H3K9me, loss of heterochromatin domains and inhibition of growth, demonstrating the importance of the intrinsic inhibition and auto-activation of Clr4 in regulating the deposition of H3K9me and in preventing epigenetic instability. Conservation of the Clr4 autoregulatory loop in other H3K9 methyltransferases and the automethylation of a corresponding lysine in the human SUV39H2 homologue16 suggest that the mechanism described here is broadly conserved.
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Project description:Small RNAs are essential for a variety of cellular functions. Argonaute (AGO) proteins are associated with all of the different classes of small RNAs, and are indispensable in small RNA-mediated regulatory pathways. AGO proteins have been identified in various types of stem cells in diverse species from plants and animals. This review article highlights recent progress on how AGO proteins and AGO-bound small RNAs regulate the self-renewal and differentiation of distinct stem cell types, including pluripotent, germline, somatic, and cancer stem cells.
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Project description:Argonaute (Ago) proteins mediate posttranscriptional gene repression by binding guide miRNAs to regulate targeted RNAs. To confidently assess Ago-bound small RNAs, we adapted a mouse embryonic stem cell system to express a single epitope-tagged Ago protein family member in an inducible manner. Here, we report the small RNA profile of Ago-deficient cells and show that Ago-dependent stability is a common feature of mammalian miRNAs. Using this criteria and immunopurification, we identified an Ago-dependent class of noncanonical miRNAs derived from protein-coding gene promoters, which we name transcriptional start site miRNAs (TSS-miRNAs). A subset of promoter-proximal RNA polymerase II (RNAPII) complexes produces hairpin RNAs that are processed in a DiGeorge syndrome critical region gene 8 (Dgcr8)/Drosha-independent but Dicer-dependent manner. TSS-miRNA activity is detectable from endogenous levels and following overexpression of mRNA constructs. Finally, we present evidence of differential expression and conservation in humans, suggesting important roles in gene regulation.
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Project description:Protection of euchromatin from invasion by gene-repressive heterochromatin is critical for cellular health and viability. In addition to constitutive loci such as pericentromeres and subtelomeres, heterochromatin can be found interspersed in gene-rich euchromatin, where it regulates gene expression pertinent to cell fate. While heterochromatin and euchromatin are globally poised for mutual antagonism, the mechanisms underlying precise spatial encoding of heterochromatin containment within euchromatic sites remain opaque. We investigated ectopic heterochromatin invasion by manipulating the fission yeast mating type locus boundary using a single-cell spreading reporter system. We found that heterochromatin repulsion is locally encoded by Set1/COMPASS on certain actively transcribed genes and that this protective role is most prominent at heterochromatin islands, small domains interspersed in euchromatin that regulate cell fate specifiers. Sensitivity to invasion by heterochromatin, surprisingly, is not dependent on Set1 altering overall gene expression levels. Rather, the gene-protective effect is strictly dependent on Set1's catalytic activity. H3K4 methylation, the Set1 product, antagonizes spreading in two ways: directly inhibiting catalysis by Suv39/Clr4 and locally disrupting nucleosome stability. Taken together, these results describe a mechanism for spatial encoding of euchromatic signals that repel heterochromatin invasion.
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