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SESAME-catalyzed H3T11 phosphorylation inhibits Dot1-catalyzed H3K79me3 to regulate autophagy and telomere silencing

ABSTRACT: The glycolytic enzyme, pyruvate kinase Pyk1 maintains telomere heterochromatin by phosphorylating histone H3T11 (H3pT11), which promotes SIR (silent information regulator) complex binding at telomeres and prevents autophagy-mediated Sir2 degradation. However, the exact action mechanism of H3pT11 is poorly understood. Here, we identify Dot1-catalyzed H3K79 tri-methylation (H3K79me3) as the downstream effector of H3pT11 and uncover how this histone crosstalk regulates autophagy and telomere silencing. Mechanistically, Pyk1-catalyzed H3pT11 directly reduces the binding of Dot1 to chromatin and inhibits Dot1-catalyzed H3K79me3, which leads to transcriptional repression of autophagy genes and reduced autophagy. Despite the antagonism between H3pT11 and H3K79me3, they synergically promote the binding of SIR complex at telomeres to maintain telomere silencing. Furthermore, we identify Reb1 as a telomere-associated factor that recruits Pyk1-containing SESAME (Serine-responsive SAM-containing Metabolic Enzyme) complex to telomere regions to phosphorylate H3T11 and prevent the invasion of H3K79me3 from euchromatin into heterochromatin to maintain telomere silencing. Together, these results uncover a novel histone crosstalk and provide insights into dynamic regulation of silent heterochromatin and autophagy in response to cell metabolism.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE210908 | GEO | 2022/11/29

REPOSITORIES: GEO

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SESAME-catalyzed H3T11 phosphorylation inhibits Dot1-catalyzed H3K79me3 to regulate autophagy and telomere silencing

Project description:The glycolytic enzyme, pyruvate kinase Pyk1 maintains telomere heterochromatin by phosphorylating histone H3T11 (H3pT11), which promotes SIR (silent information regulator) complex binding at telomeres and prevents autophagy-mediated Sir2 degradation. However, the exact action mechanism of H3pT11 is poorly understood. Here, we report that H3pT11 directly inhibits Dot1-catalyzed H3K79 tri-methylation (H3K79me3) and uncover how this histone crosstalk regulates autophagy and telomere silencing. Mechanistically, Pyk1-catalyzed H3pT11 directly reduces the binding of Dot1 to chromatin and inhibits Dot1-catalyzed H3K79me3, which leads to transcriptional repression of autophagy genes and reduced autophagy. Despite the antagonism between H3pT11 and H3K79me3, they work together to promote the binding of SIR complex at telomeres to maintain telomere silencing. Furthermore, we identify Reb1 as a telomere-associated factor that recruits Pyk1-containing SESAME (Serine-responsive SAM36 taining Metabolic Enzyme) complex to telomere regions to phosphorylate H3T11 and prevent the invasion of H3K79me3 from euchromatin into heterochromatin to maintain telomere silencing. Together, these results uncover a novel histone crosstalk and provide insights into dynamic regulation of silent heterochromatin and autophagy in response to cell metabolism.

2023-02-07 | PXD038138 | Pride

H3K79me3 ChIP-Seq at FRB-Pyk1 and WT strains under addition of DMSO treatment

Project description:The glycolytic enzyme, pyruvate kinase Pyk1 maintains telomere heterochromatin by phosphorylating histone H3T11 (H3pT11), which promotes SIR (silent information regulator) complex binding at telomeres and prevents autophagy-mediated Sir2 degradation. However, the exact action mechanism of H3pT11 is poorly understood. Here, we identify Dot1-catalyzed H3K79 tri-methylation (H3K79me3) as the downstream effector of H3pT11 and uncover how this histone crosstalk regulates autophagy and telomere silencing. Mechanistically, Pyk1-catalyzed H3pT11 directly reduces the binding of Dot1 to chromatin and inhibits Dot1-catalyzed H3K79me3, which leads to transcriptional repression of autophagy genes and reduced autophagy. Despite the antagonism between H3pT11 and H3K79me3, they synergically promote the binding of SIR complex at telomeres to maintain telomere silencing. Furthermore, we identify Reb1 as a telomere-associated factor that recruits Pyk1-containing SESAME (Serine-responsive SAM-containing Metabolic Enzyme) complex to telomere regions to phosphorylate H3T11 and prevent the invasion of H3K79me3 from euchromatin into heterochromatin to maintain telomere silencing. Together, these results uncover a novel histone crosstalk and provide insights into dynamic regulation of silent heterochromatin and autophagy in response to cell metabolism.

2022-12-10 | GSE220482 | GEO

H3T11p ChIP-Seq at FRB-Pyk1 and WT strains under addition of DMSO treatment

Project description:The glycolytic enzyme, pyruvate kinase Pyk1 maintains telomere heterochromatin by phosphorylating histone H3T11 (H3pT11), which promotes SIR (silent information regulator) complex binding at telomeres and prevents autophagy-mediated Sir2 degradation. However, the exact action mechanism of H3pT11 is poorly understood. Here, we identify Dot1-catalyzed H3K79 tri-methylation (H3K79me3) as the downstream effector of H3pT11 and uncover how this histone crosstalk regulates autophagy and telomere silencing. Mechanistically, Pyk1-catalyzed H3pT11 directly reduces the binding of Dot1 to chromatin and inhibits Dot1-catalyzed H3K79me3, which leads to transcriptional repression of autophagy genes and reduced autophagy. Despite the antagonism between H3pT11 and H3K79me3, they synergically promote the binding of SIR complex at telomeres to maintain telomere silencing. Furthermore, we identify Reb1 as a telomere-associated factor that recruits Pyk1-containing SESAME (Serine-responsive SAM-containing Metabolic Enzyme) complex to telomere regions to phosphorylate H3T11 and prevent the invasion of H3K79me3 from euchromatin into heterochromatin to maintain telomere silencing. Together, these results uncover a novel histone crosstalk and provide insights into dynamic regulation of silent heterochromatin and autophagy in response to cell metabolism.

2022-12-10 | GSE220481 | GEO

Metabolic regulation of telomere silencing by SESAME complex-catalyzed H3T11 phosphorylation

Project description:Telomeres are organized into a heterochromatin structure and maintenance of silent heterochromatin is required for chromosome stability. How telomere heterochromatin is dynamically regulated in response to stimuli remains unknown. Pyruvate kinase Pyk1 forms a complex, named SESAME (Serine-responsive SAM-containing Metabolic Enzyme complex) to regulate gene expression by phosphorylating histone H3T11 (H3pT11). Here, we identified a novel function of SESAME in regulating telomere heterochromatin structure. SESAME phosphorylates H3T11 at telomeres, which promotes SIR (silent information regulator) complex assembly at telomeres and protects Sir2 from degradation by autophagy. Moreover, SESAMEcatalyzed H3pT11 directly represses autophagy-related gene expression to further prevent autophagy-mediated Sir2 degradation. By promoting H3pT11, serine increases Sir2 protein levels and enhances telomere silencing. Loss of H3pT11 leads to reduced Sir2 and compromised telomere silencing during chronological aging. Together, our study provides insights into dynamic regulation of silent heterochromatin by histone modifications and autophagy in response to cell metabolism and aging.

2020-12-04 | GSE147050 | GEO

Metabolic regulation of telomere silencing by SESAME complex-catalyzed H3T11 phosphorylation

Project description:Metabolic regulation of telomere silencing by SESAME complex-catalyzed H3T11 phosphorylation

| PRJNA612849 | ENA

Glc7/PP1 dephosphorylates histone H3T11 to regulate autophagy and telomere silencing in response to nutrient availability

Project description:How cells adapt their gene expression to nutritional changes remains poorly understood. Histone H3T11 is phosphorylated by pyruvate kinase to repress gene transcription. Here, we identify the protein phosphatase 1 (PP1), Glc7 as the enzyme that specifically dephosphorylates H3T11. We also characterize two novel Glc7-containing subcomplexes and reveal their roles in regulating gene expression upon glucose starvation. Specifically, the Glc7-Sen1 subcomplex dephosphorylates H3T11 to activate the transcription of autophagy-related genes. The Glc7-Rif1-Rap1 subcomplex dephosphorylates H3T11 to derepress the transcription of telomere-proximal genes. Upon glucose starvation, Glc7 expression is up-regulated and more Glc7 translocates into the nucleus to dephosphorylate H3T11, leading to induction of autophagy and derepressed transcription of telomere-proximal genes. Furthermore, the functions of PP1/Glc7 and the two Glc7-containing subcomplexes are conserved in mammals to regulate autophagy and telomere structure. Collectively, our results reveal a novel mechanism to regulate gene expression and chromatin structure in response to glucose availability.

2023-04-18 | GSE227169 | GEO

eukaryotic metagenome strain:Saccharomyces cerevisiae

Project description:Metabolic regulation of telomere silencing by SESAME complex-catalyzed H3T11 phosphorylation

| PRJNA610976 | ENA

Dot1 and Histone H3K79 Methylation in Natural Heterochromatic and HML-HMR Silencing

Project description:ChIP-on-Chip of Sir proteins in WT and dot1 deletion strains

2011-02-09 | E-MEXP-3108 | biostudies-arrayexpress

Transcription profiling of yeast wild type and yku70, esc1, sir3 or rif1 knock-outs treated with splitomycin to study telomeric sequestration of SIRs

Project description:Budding yeast telomeres and cryptic mating-type loci are anchored at the nuclear envelope, forming foci that sequester Silent information regulators (SIR factors), much as heterochromatic chromocenters in higher eukaryotes sequester HP1. Here we examine the impact of such subcompartments for regulating transcription genome-wide. We show that the efficiency of subtelomeric reporter gene repression depends not only on the strength of SIR factor recruitment by cis-acting elements, but also on the accumulation of SIRs in perinuclear foci, which result from the clustering of telomeres. To monitor the effects of disrupting this subnuclear compartment, we performed microarray analyses under conditions that eliminate telomere anchoring, while preserving SIR complex integrity. We found 60 genes reproducibly misregulated. Among those with increased expression, 22% were within 20kb of a telomere, confirming that NE anchoring helps repress natural subtelomeric genes. In contrast, loci that were down-regulated were distributed over all chromosomes. Half of this ectopic repression was SIR-complex dependent. We conclude that released SIR factors can promiscuously repress transcription at nontelomeric genes despite the presence of "anti-silencing" mechanisms. Bioinformatic analysis revealed that promoters bearing the PAC (RNA Polymerase A and C promoters) or Abf1 binding consenses are consistently down-regulated by mislocalization of SIR factors. Thus, the normal telomeric sequestration of SIRs not only favors subtelomeric repression, but prevents promiscuous effects at a distinct subset of promoters. This demonstrates that patterns of gene expression can be regulated by changing the spatial distribution of repetitive DNA sequences that bind repressive factors.

2010-01-28 | E-TABM-630 | biostudies-arrayexpress

Cla4 catalyzed Set1 phosphorylation

Project description:H3K4me3 is catalyzed by the Set1/MLL family of methyltransferases, whose function in catalyzing H3K4me3 is unique. Impaired function of Set1/MLL family members can lead to many abnormalities, such as bone and nerve defects, leukemia, and even death. Although the Set1 family plays an important regulatory role in various biological processes, it is still unclear how the Set1 protein itself is regulated and how protein levels are maintained. Due to the numerous homologues, complex composition, and high molecular weight of Set1 in higher organisms, especially humans, related research is greatly limited. In brewing yeast, Set1 is the only methyltransferase that catalyzes H3K4me3 and is highly conserved between species. Therefore, yeast is an ideal model for studying the functions and mechanisms of the Set1 family. In addition, Set1 protein plays an important role in regulating gene transcription, promoting telomere silencing, and maintaining cell lifespan. The Set1 family also plays an important regulatory role in the occurrence and development of various cancers.

2023-10-24 | PXD042010 | Pride

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