Iron Drives Anabolic Metabolism Through Active Histone Demethylation and mTORC1
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ABSTRACT:
PROVIDER: PRJNA883650 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21683849.fastq.gz | Fastqsanger.gz | |||
| SRR21683850.fastq.gz | Fastqsanger.gz | |||
| SRR21683851.fastq.gz | Fastqsanger.gz | |||
| SRR21683852.fastq.gz | Fastqsanger.gz | |||
| SRR21683853.fastq.gz | Fastqsanger.gz |
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Project description:All living cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here, we report a universal eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of a high-affinity leucine transporter and RAPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency (ID) supersedes other nutrient inputs into mTORC1. This process occurs in vivo, and is not an indirect effect by canonical iron-utilizing pathways. These data demonstrate a novel mechanism of eukaryotic iron sensing through dynamic chromatin remodeling and repression of mTORC1 mediated anabolism. Due to ancestral eukaryotes sharing homologues of KDMs and mTORC1 core components, this pathway likely predated the emergence of the other kingdom-specific nutrient sensors for mTORC1.
2023-07-20 | PXD043952 | Pride
Project description:All living cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here, we report a universal eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of genes encoding high-affinity leucine transporters and RAPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency (ID) supersedes other nutrient inputs into mTORC1. This process occurs in vivo, and is not an indirect effect by canonical iron-utilizing pathways. Elevated expression of KDM3B targets is associated with reduced survival in a subset of human cancers and ID represses mTORC1 in patient-derived tumor cells and sensitizes cancer cells to chemotherapy. These data demonstrate a novel mechanism of eukaryotic iron sensing through dynamic chromatin remodeling and repression of mTORC1 mediated anabolism. Due to ancestral eukaryotes sharing homologues of KDMs and mTORC1 core components, this pathway likely predated the emergence of the other kingdom-specific nutrient sensors for mTORC1
2023-07-18 | GSE214019 | GEO
Project description:mTORC1 (mechanistic target of rapamycin complex 1) is a metabolic sensor that promotes growth when nutrients are abundant. Ubiquitous inhibition of mTORC1 extends lifespan in multiple organisms but also disrupts several anabolic processes resulting in stunted growth, slowed development, reduced fertility, and disrupted metabolism. However, it is unclear if these pleotropic effects of mTORC1 inhibition can be uncoupled from longevity. Here, we utilize the auxin-inducible degradation (AID) system to restrict mTORC1 inhibition to C. elegans neurons. We find that neuron-specific degradation of RAGA-1, an upstream activator of mTORC1, or LET-363, the ortholog of mammalian mTOR, is sufficient to extend lifespan in C. elegans. Unlike raga-1 loss of function genetic mutations or somatic AID of RAGA-1, neuronal AID of RAGA-1 robustly extends lifespan without impairing body size, developmental rate, brood size or neuronal function. Moreover, while somatic degradation of RAGA-1 alters the expression of thousands of genes, demonstrating the widespread effects of mTORC1 inhibition, neuronal degradation of RAGA-1 only results in around 200 differentially expressed genes with a specific enrichment in metabolism and stress response. Notably, our work demonstrates that targeting mTORC1 specifically in the nervous system in C. elegans uncouples longevity from growth and reproductive impairments, and that many canonical effects of low mTORC1 activity are not required to promote healthy aging. These data challenge previously held ideas about the mechanisms of mTORC1 lifespan extension and underscore the potential of promoting longevity by neuron-specific mTORC1 modulation.
2023-07-18 | GSE237060 | GEO
Project description:To explore whether iron is required for BCR-induced H3K9 demethylation during B cell activation, we performed ChIP-seq to check the H3K9me2 modification in control (iron-normal) and iron-deficient B cells
2019-05-24 | GSE131716 | GEO
Project description:Discovery, characterization, and metabolic engineering of Rieske non-heme iron monooxygenases for guaiacol O-demethylation
2021-10-25 | MSV000088263 | MassIVE
Project description:The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that stimulates macromolecule synthesis via insulin, growth factors, and oncogenic signals. mTORC1 activates anabolic pathways by inducing posttranslational modifications of metabolic enzymes, and by regulating expression through transcription and mRNA processing. However, mechanisms of how mTORC1 orchestrates these tightly connected processes remain unclear. Here, we identify FAM120A as a transcriptional co-activator that couples transcription and splicing of lipid synthesis enzymes downstream of mTORC1-SRPK2 signaling. Mechanistically, the mTORC1-activated SRPK2 phosphorylates a splicing factor SRSF1, enhancing its binding to FAM120A. FAM120A directly interacts with a lipogenic transcription factor SREBP1 at active promoters, thereby bridging newly transcribed lipogenic genes to the RNA splicing machinery. This multi-protein complex regulated by mTORC1 promotes efficient splicing and stability of lipogenic transcripts, resulting in fatty acid synthesis and cancer cell proliferation. These results elucidate FAM120A as a critical transcription co-factor that connects mTORC1-dependent gene regulation programs for anabolic cell growth.
2023-09-01 | GSE229657 | GEO
Project description:Active DNA demethylation controls transgenerational epigenetic stability
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Project description:The DNA methylation program is at the bottom layer of the epigenetic regulatory cascade of vertebrate development. While the methylation at C-5 position of the cytosine (C) residues on the vertebrate genomes is achieved through the catalytic activities of the DNA methyltransferases (DNMTs), the conversion of the methylated cytosine (5mC) could be accomplished by the combined actions of the TET enzyme and DNA repair. Interestingly, it has been found recently that the mouse and human DNMTs also possess active DNA demethylation activity in vitro in a Ca2+- and redox condition-dependent manner. We report here the study of tracking down the fate of the methyl group removed from 5mC on DNA during in vitro demethylation reaction by mouse de novo DNMTs, i.e. DNMT3A and DNMT3B. Remarkably, the methyl group becomes covalently linked to the catalytic cysteines utilized by the two de novo DNMTs in their DNA methylation reactions. Thus, the forward and reverse reactions of DNA methylations by the DNMTs may utilize the same cysteine residue(s) as the active site despite of their distinctive pathways. Secondly, we demonstrate that active DNA demethylation of a heavily methylated GFP reporter plasmid by ectopically expressed DNMT3A or DNMT3B occurs in vivo in transfected human HEK 293 cells in culture. Furthermore, the extent of DNA demethylation by the DNMTs in this cell-based system is affected by Ca2+ homeostasis as well as by mutation of their putative active cysteines. These findings substantiate the roles of the vertebrate DNMTs as double-edged swords in DNA methylation-demethylation in vitro as well as in a cellular context.
2022-02-24 | PXD003401 | Pride
Project description:The epigenomes of mammalian sperm and oocytes, characterized by gamete-specific 5-methylcytosine (5mC) patterns, are reprogrammed in early embryogenesis to establish full developmental potential. It is broadly accepted that the paternal genome is actively demethylated in the zygote while the maternal genome undergoes passive demethylation thanks to DNA replication over the subsequent cleavage divisions. Here we reveal that both maternal and paternal genomes undergo widespread active and passive demethylation in the pronuclear zygote before the first mitotic division. Whereas the passive demethylation requires DNA replication, the active demethylation relies on enzymatic oxidation of 5mC, as deletion of the DNA dioxygenase, Tet3, but not the inhibition of replication, blocks the active demethylation. At actively demethylated loci, 5mCs appear to be processed to unmodified cytosines in a manner independent of the DNA glycosylase TDG. These observations suggest the occurrence of genuine active demethylation in both parental genomes following fertilization. An extra supportive Tet3 knock-out female pronuclear sample related to experiment Series GSE56650.
2016-09-01 | E-GEOD-60777 | biostudies-arrayexpress
Project description:In this study we show that cAMP helps regulate cytosine demethylation through augmenting the intracellular labile ferrous iron pool.
2018-01-01 | GSE101153 | GEO