Recruitment of Clr4 to heterochromatin
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA925208 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23114700.fastq.gz | Fastqsanger.gz | |||
| SRR23114901.fastq.gz | Fastqsanger.gz | |||
| SRR23114802.fastq.gz | Fastqsanger.gz | |||
| SRR23114703.fastq.gz | Fastqsanger.gz | |||
| SRR23114904.fastq.gz | Fastqsanger.gz |
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Project description:To investigate the role of Clr4 recruitment, we performed FLAG-Clr4 ChIP-seq in various genetic background
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Project description:In eukaryotes, the Suv39 family of proteins tri-methylate lysine 9 of histone H3 (H3K9me) to form constitutive heterochromatin. However, how Suv39 proteins are nucleated at heterochromatin is not fully described. In the fission yeast, current models posit that Argonaute1-associated small RNAs (sRNAs) nucleate the sole H3K9 methyltransferase, Clr4/SUV39H, to centromeres. Here, we show that in the absence of all sRNAs and H3K9me, the Mtl1 and Red1 core (MTREC)/PAXT complex nucleates Clr4/SUV39H at a heterochromatic long noncoding RNA (lncRNA) at which the two H3K9 deacetylases, Sir2 and Clr3, also accumulate by distinct mechanisms. Iterative cycles of H3K9 deacetylation and methylation spread Clr4/SUV39H from the nucleation center in an sRNA-independent manner, generating a basal H3K9me state. This is acted upon by the RNAi machinery to augment and amplify the Clr4/H3K9me signal at centromeres to establish heterochromatin. Overall, our data reveal that lncRNAs and RNA quality control factors can nucleate heterochromatin and function as epigenetic silencers in eukaryotes.
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Project description:RNA surveillance (MTREC) and degradation (exosome) complexes nucleate Clr4/SUV39H at a heterochromatic long noncoding RNA, at which the two deacetylases, Sir2 and Clr3, also amass by distinct mechanisms. Iterative cycles of H3K9 deacetylation and methylation spread Clr4 from the nucleation center which with the help from RNAi establish heterochromatin. (this is like the abstract for the paper) To identify nuclear Sir2-interacting proteins, a protocol was adopted by which frozen intact nuclei suitable for biochemical purifications were released by low pressure, semi-automated cryogrinding of frozen yeast pellets after which the nuclei were isolated by differential centrifugation. From these nuclear extracts, FLAG-tagged Sir2 was purified and analyzed by nanoscale micro-capillary tandem mass spectrometry.
2024-02-25 | MSV000094160 | MassIVE
Project description:Histone H3 lysine 9 methylation (H3K9me) mediates heterochromatic gene silencing and is important for genome stability and the regulation of gene expression. 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 H3. 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 limit the spread of inappropriate H3K9me. 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 (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 growth inhibition, demonstrating the importance of the intrinsic inhibition and auto-activation of Clr4 in regulating the deposition of H3K9me and in preventing epigenetic instability. Together, conservation of the Clr4 autoregulatory loop in other H3K9 methyltransferases and the automethylation of a corresponding lysine in the human SUV39H2 homologue suggest that the mechanism described here is broadly conserved.
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Project description:Heterochromatin, a highly compact chromatin state characterized by histone H3 lysine 9 methylation (H3K9me) and HP1 protein binding, epigenetically silences the underlying DNA and influences the expression of neighboring genes. Therefore the sites of heterochromatin assembly and its subsequent spreading are generally precisely determined. Here we show that in fission yeast, the combined absence of anti-silencing factors Mst2 and Epe1 results in uncontrolled heterochromatin spreading and severe growth defects. Interestingly, these cells quickly recover by accumulating H3K9me at the clr4+ locus, which encodes the H3K9 methyltransferase essential for heterochromatin assembly, thereby leading to reduced expression of Clr4 to restrain heterochromatin spreading. Preventing H3K9me at the clr4+ locus resulted in the accumulation of H3K9me at the rik1+ locus, which encodes another component of the Clr4 complex essential for H3K9me. Our results demonstrate that promiscuous heterochromatin assembly enables fast adaptation in response to changes in chromatin landscape and illustrate a negative feedback mechanism by which cells counteract toxic heterochromatin accumulation.
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Project description:Regulation of heterochromatin is critical for genome stability. Different states of methylated H3K9 have been discovered with distinct roles in heterochromatin formation and silencing. However, the control of the transition from H3K9me2 to H3K9me3 is still unclear. Here we investigate the role of the conserved bromodomain AAA-ATPase, Abo1, involved in maintaining the global nucleosome organization in fission yeast. We identified several key factors involved in heterochromatin silencing to interact genetically with Abo1: the histone deacetylase Clr3, the H3K9 methyltransferase Clr4, and the HP1 homologue Swi6. Cells lacking Abo1 display an imbalance of H3K9me2 and H3K9me3 in heterochromatin. In abo1∆ cells, the centromeric constitutive heterochromatin had increased H3K9me2 but decreased H3K9me3 levels compared to wild type. In contrast, facultative heterochromatin regions, show both reduced H3K9me2 and H3K9me3 levels in abo1∆. Genome-wide analysis showed that abo1∆ cells have silencing defects in both centromeres and subtelomeres, but not in a subset of heterochromatin islands. Our work uncovers a new role for Abo1 in supporting Clr4 activity and allowing for the transition of H3K9me2 to H3K9me3 in telomeric and centromeric heterochromatin.
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Project description:H3K9me2 profiles and Fft3 occupancy in fission yeast. Heterochromatin can be epigenetically inherited in cis, leading to stable maintenance of gene expression states. However, the mechanisms underlying heterochromatin inheritance remain unclear. Here we identify Fft3, a homolog of the mammalian SMARCAD1 Snf2 chromatin remodeler, as a factor uniquely required for heterochromatin inheritance, rather than for de novo assembly. Importantly, we find that Fft3 bound to heterochromatic loci suppresses turnover of parental histones and is critical for the epigenetic transmission of heterochromatin in cycling cells. Surprisingly, Fft3 also localizes to several euchromatic loci where it is required for proper replication progression. Fft3 promotes nucleosome stability at these loci to prevent R-loop formation that can impede replication machinery. Strikingly, overexpression of the Clr4/Suv39h methyltransferase, which is also required for efficient replication through these loci, suppresses phenotypes associated with the loss of Fft3. Thus, we find that Fft3 promotes nucleosome stability to facilitate heterochromatin inheritance and also acts in parallel to Clr4 ensure proper replication of euchromatic regions.
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