A phosphorylation switch within the Mediator subunit MED15 controls cellular senescence and cognitive decline
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ABSTRACT:
PROVIDER: PRJNA1201231 | ENA |
REPOSITORIES: ENA
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Project description:A hallmark of aging is chronic systemic inflammation, which is exacerbated by the hypersecretory aging phenotype known as the senescence-associated secretory phenotype (SASP). How the SASP is initiated to accelerate tissue inflammation and aging is an outstanding question in ageing biology. Here, we showed that phosphorylation of the mediator subunit MED15 at T603 is able to control the SASP and aging. Transforming growth factor-β (TGFβ) selectively induces CDK1-mediated MED15 T603 phosphorylation to control SASP gene expression. The MED15 T603 dephosphorylated mutant (T603A) inhibits the SASP and cell senescence, whereas the T603 phosphorylation-mimicking mutant (T603D) has the opposite effect. Mechanistically, forkhead box protein A1 (FOXA1) preferentially binds to unphosphorylated but not phosphorylated MED15 at T603 to suppress SASP gene expression. Notably, aging mice harboring dephosphorylated mutation in this phosphosite exhibit improved learning and memory through the attenuation of the SASP across tissues. Overall, our study indicates that MED15 T603 phosphorylation serves as a control switch for SASP production, which underlies tissue aging and cognitive decline and provides a novel target for age-related pathology.
2025-08-27 | GSE285138 | GEO
Project description:A hallmark of aging is chronic systemic inflammation, which is exacerbated by the hypersecretory aging phenotype known as the senescence-associated secretory phenotype (SASP). How the SASP is initiated to accelerate tissue inflammation and aging is an outstanding question in ageing biology. Here, we showed that phosphorylation of the mediator subunit MED15 at T603 is able to control the SASP and aging. Transforming growth factor-β (TGFβ) selectively induces CDK1-mediated MED15 T603 phosphorylation to control SASP gene expression. The MED15 T603 dephosphorylated mutant (T603A) inhibits the SASP and cell senescence, whereas the T603 phosphorylation-mimicking mutant (T603D) has the opposite effect. Mechanistically, forkhead box protein A1 (FOXA1) preferentially binds to unphosphorylated but not phosphorylated MED15 at T603 to suppress SASP gene expression. Notably, aging mice harboring dephosphorylated mutation in this phosphosite exhibit improved learning and memory through the attenuation of the SASP across tissues. Overall, our study indicates that MED15 T603 phosphorylation serves as a control switch for SASP production, which underlies tissue aging and cognitive decline and provides a novel target for age-related pathology.
2025-08-27 | GSE285137 | GEO
Project description:A phosphorylation switch within the Mediator subunit MED15 controls cellular senescence and cognitive decline [ChIP-seq]
| PRJNA1201230 | ENA
Project description:The multiprotein Mediator complex is an important regulator of RNA polymerase II-dependent genes in eukaryotic cell. In contrast to the situation in many other eukaryotes, the conserved Med15 protein is not a stable component of Mediator isolated from fission yeast. We now demonstrate that Med15 exists in a protein complex together with Hrp1, an ATP-dependent chromatin remodeling protein. The Med15/Hrp1 subcomplex is not a component of the core Mediator complex, but can interact with the repressive L-Mediator conformation. Deletion of MED15 and HRP1 cause similar effects on global steady-state levels of mRNA, but only MED15 is required for galactose-dependent activation of the inv1 gene. Hrp1 has been found in complex with other proteins and genome-wide analysis demonstrates that Med15 only associates with a distinct subset of Hrp1-bound gene promoters. Global analysis reveals that Hrp1-binding normally is associated with increased histone H3 density, but at promoters also bound by Med15, histone H3 density is instead increased. Our findings reveal that Med15 functions as a separate entity in fission yeast and indicate that the function and organization of the Mediator complex may differ significantly between eukaryotes. Keywords: ChIP-chip
2010-09-21 | GSE10079 | GEO
Project description:The Mediator is composed of multiple of proteins in the head, body, tail and CDK subunits conserved from yeast to humans. However, not all the components are required for transcription. Components of the tail subunit are not essential but to varying degrees are required for changes in transcription to stress. While some stresses are familiar such as heat, desiccation, and starvation, others are exotic yet elicit a physical stress response. MCHM is a hydrotrope that induces growth arrest in yeast. By exploiting genetic variation, specifically in Med15, between yeast strains, we found that Med15 with the polyQ expansion conferred MCHM sensitivity. This sensitivity was not from a loss of function as the reciprocal hemizygous hybrids were all sensitive, suggesting that there is an incompatibility between Mediator complexes from genetic divergent yeast strains. Transcriptomics from yeast expressing the incompatible Med15 changed expression in diverse pathways. Expansion of polyQ tracts in Med15 resulted in multiple isoforms which were mostly from likely post-translational modifications. Stability of Med15 was dependent on Ydj1, a chaperone and the incompatible Med15 allele was expressed at lower levels and less stable than the compatible Med15 allele. Med15 is tethered to the rest of the Mediator complex via Med2 and 3. Deletion of either Med2 or Med3 changes the Med15 isoform patterns in the in a similar manner whereas deletion of Med5, a distal component of the tail did not change the pattern. The med2 and 3 mutants are similarly sensitive to MCHM while med5 mutants are not. Differences between the Med15 alleles extend to responses to different stresses. Whereas the incompatible allele of Med15 improved growth to chemicals that produce free radicals, and the compatible allele of Med15 improved growth to reducing agents, caffeine, and hydroxyurea. This may reflect the positive and negative role that Med15 has in transcription.
2020-04-06 | GSE129898 | GEO
Project description:Mediator, a co-regulator required for RNA pol II activity, interacts with tissue-specific transcription factors to regulate development and maintain homeostasis. We sought to understand whether Mediator subunit MED15 acts as a node that controls tissue-specific gene expression, using pancreatic insulin-producing β-cell maturation as a model. We found Med15 to be expressed during mouse pancreatic organogenesis and β-cell maturation; moreover, islets from human T2D donors feature reduced MED15 expression. Loss of Med15 in mouse β-cells caused defects in maturation without affecting β-cell mass or insulin expression. ChIP-seq and co-immunoprecipitation analyses determined that Med15 binds β-cell transcription factors Nkx6-1 and NeuroD1 to regulate key β-cell maturation genes. Human embryonic stem cell derived β-like cells, genetically engineered to express high levels of MED15, had increased maturation markers and improved insulin secretion. We provide the first evidence of the importance of Mediator in β-cell maturation and demonstrate an additional layer of control that tunes transcription factor function.
2024-09-10 | GSE137145 | GEO
Project description:Mediator subunits Med17 (Srb4) and Med15 (Gal11) were subjected to ChIP in wild type yeast, med18 (srb5), med20 (srb2), and med2 med3 med15 (triple mutant) yeast, all in kin28-anchor away yeast after 1 hr rapamycin treatment to evict Kin28 from the nucleus. This results in inactivation of Kin28, which reduces Mediator turnover at promoters and allows stronger Mediator ChIP signal at promoters. <br></br>Both Med17 and Med15 were tagged with myc and precipitated using the monoclonal antibody against c-myc. Please note that a specific control for rapamycin treatment was not performed in this experiment, as that has been well documented in the literature for this experiment, using what is called the anchor away method. The untagged sample is a control for non-specific immunoprecipitation.
2017-12-01 | E-MTAB-5824 | biostudies-arrayexpress
Project description:Type 2 diabetes (T2D) is consistently associated with an elevated risk of cognitive decline and dementia. The underlying molecular mechanisms relating T2D to cognitive decline remain unclear, impeding the ability to detect the earliest stages of cognitive decline in older adults with T2D, consequently hindering advancement of preventive interventions. This study compared quantitative alterations in glycoproteoforms, represented by tryptic glycopeptiforms—specific glycan compositions on amino acid sites of proteins—in older T2D adults. We utilized label free, mass spectrometry-based glycoproteomics to analyze protein N-glycosylation and glycation patterns in serum samples, collected at two time points (T1 and T2), an average 52 months apart, from two initially cognitively healthy T2D groups. One group was comprised of individuals who experienced cognitive decline (“decliners”; N=8), and the other, of individuals who maintained normal cognition (“non-decliners”; N=14) over time. Comparison of these two groups revealed distinct patterns for glycosylation and glycation. Glycosylation primarily affected platelet function pathways. Glycation was also involved in immune system and platelet function along with various metabolic pathways. These findings suggest that aberrant glycoproteomic modifications may contribute to the development of cognitive impairment in T2D and may serve as potential early biomarkers. Further research is warranted to elucidate the functional implications of glycopeptiform modifications in T2D-related cognitive decline.
2025-02-16 | PXD050780 | Pride
Project description:The yeast Mediator complex can be divided into three modules, designated Head, Middle and Tail. Tail comprises the Med2, Med3, Med5, Med15 and Med16 protein subunits, which are all encoded by genes that are individually non-essential for viability. In cells lacking Med16, Tail is displaced from Head and Middle. However, inactivation of MED5/MED15 and MED15/MED16 are synthetically lethal, indicating that Tail performs essential functions as a separate complex even when it is not bound to Middle and Head. We have used the N-Degron method to create temperature sensitive (ts) mutants in the Mediator tail subunits Med5, Med15 and Med16 to study the immediate effects on global gene expression when each subunit is individually inactivated, and when MED5/15 or MED15/16 are inactivated together. All Degron constructs were expressed from their normal chromosomal location under the control of their respective endogenous promoters. We isolated RNA from each strain as early as 45 minutes after changing from the permissive to the restrictive growth conditions to minimize possible secondary effects on gene expression that are not directly caused by the Degron construct(s).
2013-06-07 | E-GEOD-47712 | biostudies-arrayexpress
Project description:The yeast Mediator complex can be divided into three modules, designated Head, Middle and Tail. Tail comprises the Med2, Med3, Med5, Med15 and Med16 protein subunits, which are all encoded by genes that are individually non-essential for viability. In cells lacking Med16, Tail is displaced from Head and Middle. However, inactivation of MED5/MED15 and MED15/MED16 are synthetically lethal, indicating that Tail performs essential functions as a separate complex even when it is not bound to Middle and Head. We have used the N-Degron method to create temperature sensitive (ts) mutants in the Mediator tail subunits Med5, Med15 and Med16 to study the immediate effects on global gene expression when each subunit is individually inactivated, and when MED5/15 or MED15/16 are inactivated together.
2013-06-07 | GSE47712 | GEO