Coordinated Histone Methylation Loss and MYC Activation Promote Translational Capacity Under Amino Acid Restriction
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ABSTRACT:
PROVIDER: PRJNA1262742 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33558161_1.fastq.gz | Fastqsanger.gz | |||
| SRR33558161_2.fastq.gz | Fastqsanger.gz | |||
| SRR33558162_1.fastq.gz | Fastqsanger.gz | |||
| SRR33558162_2.fastq.gz | Fastqsanger.gz | |||
| SRR33558163_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Epigenetic mechanisms underlying cellular adaptation to and recovery from nutrient deficiency are incompletely understood. Here, we report an adaptive epigenetic response to amino acid (AA) restriction that primes cells for rapid recovery. Depriving human cells of AAs led to selective loss of histone H4 lysine 20 monomethylation (H4K20me1) from gene bodies and increased MYC binding at promoters genome-wide, with strongest effects at ribosomal protein and translation initiation genes. Although AA restriction reduced overall protein synthesis, it was accompanied by increased translational capacity through upregulation of protein synthesis genes and accumulation of monomeric ribosomes. Combined SETD8, the H4K20 methyltransferase, depletion and MYC over-expression in nutrient-rich media was necessary and sufficient to recapitulate the transcriptional and functional effects of AA restriction. These findings suggest that cells respond to AA deprivation through coordinated chromatin and transcriptional changes that anticipate nutrient restoration and promote rapid recovery of protein synthesis when AAs are replenished.
2025-05-15 | GSE297112 | GEO
Project description:Histone demethylation and MYC activation enhance translational capacity in response to amino acid restriction
| PRJNA391293 | ENA
Project description:Nutrient limitation may elicit adaptive epigenetic changes but the nature and mechanisms of the cellular response to specific nutrient deficiencies are incompletely understood. We report that depriving human cells of amino acids (AAs) induces specific loss of H4K20me1 from gene bodies and elevated binding of c-MYC at promoters genome-wide. These effects are most pronounced at ribosomal protein and translation initiation genes, which are upregulated, leading to enhanced protein synthetic capacity. Combination of H4K20 methyltransferase depletion and c-MYC over-expression in rich media is required and sufficient to recapitulate the effects of AA restriction. Our data reveal an unexpected and epigenetically implemented increase in translational capacity when AAs are limiting, likely to safeguard the proteome by making effective use of limited resources.
2024-12-31 | GSE100303 | GEO
Project description:Nutrient limitation may elicit adaptive epigenetic changes but the nature and mechanisms of the cellular response to specific nutrient deficiencies are incompletely understood. We report that depriving human cells of amino acids (AAs) induces specific loss of H4K20me1 from gene bodies and elevated binding of c-MYC at promoters genome-wide. These effects are most pronounced at ribosomal protein and translation initiation genes, which are upregulated, leading to enhanced protein synthetic capacity. Combination of H4K20 methyltransferase depletion and c-MYC over-expression in rich media is required and sufficient to recapitulate the effects of AA restriction. Our data reveal an unexpected and epigenetically implemented increase in translational capacity when AAs are limiting, likely to safeguard the proteome by making effective use of limited resources.
2024-12-31 | GSE100302 | GEO
Project description:Correct charging of tRNAs with their corresponding amino acid is crucial for accurate translation of the genetic code into proteins. However, a growing body of evidence shows that unicellular organisms (bacteria and yeast) can sacrifice translational fidelity to preserve protein synthesis under deprivation of specific essential amino acids.1 Several weeks ago, Pataskar and colleagues described the first instance of codon reassignments caused by amino acid restriction in mammalian cells. Specifically, when human cancer cells were deprived of tryptophan (W), tRNATrp was misacylated with the structurally similar amino acid phenylalanine (F) by tryptophanyl-tRNA synthetase (WARS1), resulting in W>F substitutions in synthesized proteins.2 The authors show that W>F substitutions do preserve translation, but generally result in dysfunctional proteins and that presentation of W>F peptides stimulates T cell-mediated killing. Together this would impair survival of cancer cells that incorporate W>F substitutions in their proteome.2 In the context of growing interest in amino acid depletion diets and related disorders,2 we wondered whether amino acid substitutions are restricted to pathological states like cancer or may represent a more generalized mechanism to maintain translation despite unfavorable circumstances. It is known that ARSs can misactivate tRNAs with structurally similar amino acids3, but editing activity ensures extreme specificity under physiological conditions.4,5 Given the structural similarities between isoleucine and valine, we speculated that isoleucyl-tRNA synthetase (IARS1) would misacylate tRNAIle with valine under isoleucine restriction, leading to I>V substitutions in the proteome. Not only did these substitutions occur in healthy primary human cells, but they also preserved translation and promoted cell viability upon nutritional stress.
2024-11-26 | PXD033426 | Pride
Project description:Cysteine is a semi-essential amino acid provided by dietary intake of mainly meat, eggs and whole grains or via the amino acid methionine. The majority of dietary cystine is absorbed in the small intestine and can be used for protein synthesis or converted to taurine and glutathione. Since there is a trend towards adopting a vegetarian/vegan diet, which is low in cysteine, in this study, we investigate the effect of dietary cystine restriction on intestinal epithelial layer function. Mice (8/group) received a normal diet or a diet low in cystine for 2 weeks. We observed no changes in plasma methionine, cysteine, taurine or glutathione levels after 2 weeks. Stem cell markers as well as the proliferation marker Ki67 were or tended to be increased upon cystine restriction. Gene set enrichment analysis reveals enrichment of Wnt signaling in the small intestine of mice on the low cystine diet. These proliferative effects were not observed in the colon, and are thus specific for the small intestine. In the colon, we observed that dietary cystine restriction results in an increase in the number of goblet cells but no significant changes in the thickness of the mucus barrier or in its protective capacity. There was no difference in the microbiome between the normal and low cystine diet. Overall, we cannot conclude if dietary cystine restriction is beneficial, since increased proliferation and goblet cells can indicate a potential for damage repair, nevertheless hyperproliferation has the potential to induce cancer as well.
2023-09-01 | GSE234566 | GEO
Project description:Dietary protein dilution (DPD) promotes metabolic remodelling and health but the precise nutritional components driving this response remain elusive. Here we demonstrate that dietary amino acids (AA) are sufficient and necessary to drive the response to DPD. In particular, the restriction of dietary essential AA (EAA) supply, but not non-EAA, drives the systemic metabolic response to total AA deprivation. Furthermore, systemic deprivation of Thr and Trp, independent of total AA supply, are both adequate and necessary to confer the systemic metabolic response to both diet, and genetic AA-transport loss, driven AA restriction. Thr is also potentially limiting in low-protein diet fed humans, and dietary Thr restriction (DTR) retarded the development of obesity-associated metabolic dysfunction in mice. Liver-derived fibroblast growth factor 21 was required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of Thr biosynthetic capacity reversed the systemic response to DTR. Taken together, our studies demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD.
2020-06-15 | PXD018205 | Pride
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-12-31 | GSE100304 | GEO
Project description:Cellular metabolism is an integral component of cellular adaptation to stress, consequently, metabolism plays a pivotal role in the resistance of cancer cells to a range of treatment modalities. Radiotherapy is used to treat approximately half of all cancer patients, however, most are either inherently radioresistant or acquire resistance over time. Effective radiotherapy relies on generating an overwhelming burden of DNA damage which triggers cell death. In response to radiotherapy cancer cells engage antioxidant and DNA repair mechanisms which mitigate and remove DNA damage, facilitating cancer cell survival. Given the reliance of these resistance mechanisms on amino acid metabolism we hypothesised that controlling the availability of the exogenous amino acids serine and glycine would be an effective strategy to radiosensitive cancer cells. Here we show that serine and glycine restriction sensitised a range of cancer cell lines, patient derived organoids and syngeneic mouse tumour models to radiotherapy. Comprehensive metabolomic analysis of central carbon metabolism revealed that amino acid restriction impacted not only glutathione and nucleotide synthesis but had an unexpected impact on the TCA cycle and antagonised a key cellular redox response to radiotherapy mediated by reductive carboxylation.
2022-11-02 | GSE190668 | GEO
Project description:Translational control is a widespread mode of gene regulation in organisms ranging from bacteria to mammals. Computational models posit that translational control of protein expression during elongation is exerted through a traffic jam of multiple ribosomes at ribosome pause sites on mRNAs. Yet neither the in vivo frequency of ribosome traffic jams nor the contribution of such traffic jams to protein expression has been measured in any organism. Here we show that upon starvation for single amino acids in the bacterium Escherichia coli, ribosome traffic jams are pervasive across the transcriptome, but they occur at only a subset of codons cognate to the limiting amino acid, and their severity is determined by the translation efficiency of mRNAs. Surprisingly, a computational model based on the observed traffic jams at ribosome pause sites is quantitatively inconsistent with measured protein synthesis rates. By comparison, a model incorporating abortion of protein synthesis at ribosome pause sites in addition to ribosome traffic jams predicts protein synthesis rate with higher accuracy. Consistent with the latter model, a significant fraction of the nascent polypeptides at ribosome pause sites is degraded through the activity of the transfer-messenger RNA during amino acid starvation in E. coli. Our work provides a minimal, experimentally-constrained model for predicting protein expression from ribosome dynamics, and it suggests the existence of a trade-off between the cellular translational capacity and the processivity of protein synthesis in vivo. 6 samples for ribosome profiling and 5 samples for total mRNA profiling
2014-05-15 | E-GEOD-51052 | biostudies-arrayexpress