Demethylation of the Protein Phosphatase PP2A Promotes Demethylation of Histones to Enable Their Function as a Methyl Group Sink

Ye, Cunqi; Sutter, Benjamin M.; Wang, Yun; Kuang, Zheng; Zhao, Xin; Yu, Yonghao; Tu, Benjamin P.

doi:10.1016/j.molcel.2019.01.012

Cited by 38 publications

(38 citation statements)

References 55 publications

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“…Adenosine in the presence of adenosine kinase increases the synthesis of AMP in the liver and thus altering the AMP/ATP ratio affecting AMPK activation. Further, current study provides indirect but not direct evidence that l ‐Met through action of SAM regulate the activity of phosphatases and thereby AMPK phosphorylation …”

Section: Discussionmentioning

confidence: 63%

Dietary Supplementation of Methyl Donor l‐Methionine Alters Epigenetic Modification in Type 2 Diabetes

Navik

Sheth

Kabeer

et al. 2019

Molecular Nutrition Food Res

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Scope The aim of the current study is to evaluate whether l‐methionine supplementation (l‐Met‐S) improves type 2 diabetes‐induced alterations in glucose and lipid metabolism by modulating one‐carbon metabolism and methylation status. Methods and Results Diabetes is induced in male Sprague–Dawley rats using high‐fat diet and low dose streptozotocin. At the end of study, various biochemical parameters, immunoblotting, qRT‐PCR and ChIP‐qPCR are performed. The first evidence that l‐Met‐S activates p‐AMPK and SIRT1, very similar to “metformin,” is provided. l‐Met‐S improves the altered key one‐carbon metabolites in diabetic rats by modulating methionine adenosyl transferase 1A and cystathione β synthase expression. qRT‐PCR shows that l‐Met‐S alleviates diabetes‐induced increase in Forkhead transcription factor 1 expression and thereby regulating genes involved in glucose (G6pc, Pdk4, Pklr) and lipid metabolism (Fasn). Interestingly, l‐Met‐S inhibits the increased expression of DNMT1 and also prevents methylation of histone H3K36me2 under diabetic condition. ChIP assay shows that persistent increase in abundance of histone H3K36me2 on the promoter region of FOXO1 in diabetic rats and it is recovered by l‐Met‐S. Conclusion The first evidence that dietary supplementation of l‐Met prevents diabetes‐induced epigenetic alterations and regulating methionine levels can be therapeutically exploited for the treatment of metabolic diseases is provided.

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Section: Discussionmentioning

confidence: 63%

Dietary Supplementation of Methyl Donor l‐Methionine Alters Epigenetic Modification in Type 2 Diabetes

Navik

Sheth

Kabeer

et al. 2019

Molecular Nutrition Food Res

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“…To identify potential Rim15-mediated phosphorylation sites of Rph1, nine phosphorylation sites reported in previous studies will be further analyzed ( Supplementary Figure S7B ). The reason why we chose those sites as they became phosphorylated only under nutrient stress conditions ( 25 , 34 ). Each serine residue of phosphorylated site on Rph1 was mutated to alanine (A) or aspartic acid (D) to represent phospho-defective mutant or phospho-mimetic mutant, respectively.…”

Section: Resultsmentioning

confidence: 99%

Rph1 coordinates transcription of ribosomal protein genes and ribosomal RNAs to control cell growth under nutrient stress conditions

Shu

Chen

Yin

et al. 2020

Nucleic Acids Research

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Abstract Coordinated regulation of ribosomal RNA (rRNA) synthesis and ribosomal protein gene (RPG) transcription by eukaryotic RNA polymerases (RNAP) is a key requirement for growth control. Although evidence for balance between RNPI-dependent 35S rRNA production and RNAPII-mediated RPG transcription have been described, the molecular basis is still obscure. Here, we found that Rph1 modulates the transcription status of both rRNAs and RPGs in yeast. We show that Rph1 widely associates with RNAPI and RNAPII-transcribed genes. Deletion of RPH1 remarkably alleviates cell slow growth caused by TORC1 inhibition via derepression of rRNA and RPG transcription under nutrient stress conditions. Mechanistically, Rim15 kinase phosphorylates Rph1 upon rapamycin treatment. Phosphorylation-mimetic mutant of Rph1 exhibited more resistance to rapamycin treatment, decreased association with ribosome-related genes, and faster cell growth compared to the wild-type, indicating that Rph1 dissociation from chromatin ensures cell survival upon nutrient stress. Our results uncover the role of Rph1 in coordination of RNA polymerases-mediated transcription to control cell growth under nutrient stress conditions.

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“…The key elements in this transformation include tRNA thiolation mediated routing of carbon-flux towards the PPP as well as maintaining overall metabolic homeostasis (41), Gcn4-mediated increased biosynthesis of amino acids and nucleotides (14,22), maintaining translation capacity (22), balancing phospholipid and histone methylation (17), and SAM-mediated increased translation via the activation of the TORC1 pathway (13,15,16). The role of the methyltransferase Ppm1, and methylation dependent PP2A activity in the methionine-induced growth program appears to be central, since methylated PP2A activates the TORC1 pathway (13), global histone methylation (17,61), and controls anabolic precursor synthesis via the activation of Gcn4 (as seen in this study). Given the evolutionary conservation of all these processes observed in yeast and mammals, including the degradation of ATF4 via a phosphorylation dependent interaction with a ubiquitin ligase (62), it will be interesting to evaluate the roles of methylated PP2A dependent signaling outputs in relevant contexts of growth regulation in healthy and diseased tissue.…”

Section: Discussionmentioning

confidence: 99%

Methylated PP2A stabilizes Gcn4 to enable a methionine-induced anabolic program

Walvekar

Kadamur

Sreedharan

et al. 2020

Preprint

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Methionine, through S-adenosylmethionine, activates multifaceted growth programs where ribosome biogenesis, carbon metabolism, amino acid and nucleotide biosynthesis are induced. This growth program requires activity of the Gcn4 transcription factor (called ATF4 in mammals), which enables metabolic precursor supply essential for anabolism. Here, we discover how the Gcn4 protein is induced by methionine, despite conditions of high translation and anabolism. This induction mechanism is independent of transcription, as well as the conventional Gcn2/eIF2α mediated increased translation of Gcn4. Instead, when methionine is abundant, Gcn4 ubiqitination and therefore degradation is reduced, due to the decreased phosphorylation of this protein. This Gcn4 stabilization is mediated by the activity of the conserved methyltransferase, Ppm1, which specifically methylates the catalytic subunit of protein phosphatase PP2A when methionine is abundant. This methylation of PP2A shifts the balance of Gcn4 to a dephosphorylated state, which stabilizes the protein. The loss of Ppm1, or PP2A-methylation destabilizes Gcn4 when methionine is abundant, and the Gcn4-dependent anabolic program collapses. These findings reveal a novel signaling and regulatory axis, where methionine directs a conserved methyltransferase Ppm1, via its target phosphatase PP2A, to selectively stabilize Gcn4. Thereby, when methionine is abundant, cells conditionally modify a major phosphatase in order to stabilize a metabolic master-regulator and drive anabolism.

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Demethylation of the Protein Phosphatase PP2A Promotes Demethylation of Histones to Enable Their Function as a Methyl Group Sink

Abstract: Highlights d SAM depletion leads to sequential demethylation of PP2A and histones d Demethylation of PP2A spares SAM by limiting histone methylation d PP2A-regulated phosphorylation of demethylase Rph1 promotes binding to chromatin d H3K36 methylation is regulated by PP2A Cdc55

Cited by 38 publications

References 55 publications

Dietary Supplementation of Methyl Donor l‐Methionine Alters Epigenetic Modification in Type 2 Diabetes

Dietary Supplementation of Methyl Donor l‐Methionine Alters Epigenetic Modification in Type 2 Diabetes

Rph1 coordinates transcription of ribosomal protein genes and ribosomal RNAs to control cell growth under nutrient stress conditions

Methylated PP2A stabilizes Gcn4 to enable a methionine-induced anabolic program

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