ATF4 mediates cold-induced adipose tissue browning by regulating MTHFD2 expression
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ABSTRACT:
PROVIDER: PRJNA1076873 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27982439_1.fastq.gz | Fastqsanger.gz | |||
| SRR27982439_2.fastq.gz | Fastqsanger.gz | |||
| SRR27982440_1.fastq.gz | Fastqsanger.gz | |||
| SRR27982440_2.fastq.gz | Fastqsanger.gz | |||
| SRR27982441_1.fastq.gz | Fastqsanger.gz |
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Project description:In mammals, adaptation to cold environments involves browning of inguinal white adipose tissue (iWAT) to enhance adaptive thermogenesis and maintain body temperature. Immune cells that reside in the adipose tissue are involved in iWAT browning. However, the mechanism by which thermogenesis regulates immune cell composition remains elusive. Here, we revealed that cold-induced activating transcription factor 4 (ATF4) is necessary for maintaining the immune cell composition and supporting iWAT browning. ATF4 and integrated stress response-related genes were highly expressed in iWAT following acute cold exposure. Mice lacking ATF4 exhibited less cold-induced iWAT browning and lower CL316,243-induced oxygen consumption. Mechanistically, the depletion of ATF4 leads to the accumulation of mitochondrial oxidative stress due to the reduction of MTHFD2, a mitochondrial one-carbon metabolism enzyme that contributes to the maintenance of the mitochondrial redox balance. This leads to higher levels of pro-inflammatory cytokines and shifts in adipose tissue macrophage polarization. Together, our findings highlight the critical role of ATF4 in maintaining oxidative stress and adipose tissue inflammatory signaling, thus supporting iWAT browning.
2025-02-15 | GSE255840 | GEO
Project description:Maintaining redox balance is crucial for mitochondrial homeostasis. During browning of white adipocytes, both the quality and quantity of mitochondria undergo dramatic changes. However, the mechanisms controlling the redox balance in the mitochondria during this process remain unclear. In this study, we demonstrate that thermogenic activation occurs before mitochondrial biogenesis during cold-induced browning of inguinal white adipose tissue (iWAT) and is accompanied by increased mitochondrial stress and integrated stress response (ISR) signaling. Specifically, cold exposure enhances the expression of ATF4, an ISR effector. Adipocyte-specific deletion of ATF4 results in increased energy expenditure, but paradoxically leads to a lower core body temperature, and heightened pro-inflammation in iWAT after cold exposure, which is restored by the antioxidant, MitoQ. Mechanistically, ATF4 regulates the redox balance through MTHFD2, an enzyme involved in mitochondrial redox homeostasis by NADPH generation. Cold exposure upregulates MTHFD2 expression in an ATF4-dependent manner, and its inhibition by DS18561882 in vivo leads to impaired cold- induced mitochondrial respiration similar to the effects of ATF4 loss. These findings suggest that ATF4 is essential for redox balance via MTHFD2, thereby affecting tissue homeostasis during iWAT browning.
2025-05-13 | GSE294416 | GEO
Project description:Regulation of Redox Homeostasis by ATF4-MTHFD2 Axis during White Adipose Tissue Browning
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Project description:To investigate the white-browning effect in inguinal WAT tissue by cold-treated and fasting-treated
2022-11-09 | GSE217290 | GEO
Project description:Subcellular compartmentalization of metabolic enzymes may elicit specific cellular functions by establishing a unique metabolic environment. Indeed, the nuclear translocation of certain metabolic enzymes is required for epigenetic regulation and gene expression control. Here, we reveal that, in cancer cells, the mitochondrial enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) localizes in the nucleus during the G2-M phase of the cell cycle to secure mitosis progression. Nuclear MTHFD2 interacts with proteins involved in mitosis regulation and centromere stability, including the methyltransferases KMT5A and DNMT3B. Loss of MTHFD2 induces centromere overexpression and severe methylation defects, and impedes correct mitosis completion. As a consequence, MTHFD2 deficient cells accumulate chromosomal aberrations arising from chromosome congression and segregation defects. Blocking the catalytic nuclear function of MTHFD2 recapitulates the phenotype observed in MTHFD2 deficient cells, attributing to nuclear MTHFD2 an enzymatic active role in controlling mitosis. Our discovery uncovers a nuclear moonlighting role for the cancer target MTHFD2, and emphasizes that cancer metabolism rewiring may encompass the relocation of metabolic enzymes to alternative subcellular compartments.
2024-11-28 | PXD041821 | Pride
Project description:Subcellular compartmentalization of metabolic enzymes may elicit specific cellular functions by establishing a unique metabolic environment. Indeed, the nuclear translocation of certain metabolic enzymes is required for epigenetic regulation and gene expression control. Here, we reveal that, in cancer cells, the mitochondrial enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) localizes in the nucleus during the G2-M phase of the cell cycle to secure mitosis progression. Nuclear MTHFD2 interacts with proteins involved in mitosis regulation and centromere stability, including the methyltransferases KMT5A and DNMT3B. Loss of MTHFD2 induces centromere overexpression and severe methylation defects, and impedes correct mitosis completion. As a consequence, MTHFD2 deficient cells accumulate chromosomal aberrations arising from chromosome congression and segregation defects. Blocking the catalytic nuclear function of MTHFD2 recapitulates the phenotype observed in MTHFD2 deficient cells, attributing to nuclear MTHFD2 an enzymatic active role in controlling mitosis. Our discovery uncovers a nuclear moonlighting role for the cancer target MTHFD2, and emphasizes that cancer metabolism rewiring may encompass the relocation of metabolic enzymes to alternative subcellular compartments.
2024-07-26 | GSE232307 | GEO
Project description:Lung cancer is leading cause of cancer-related death in the world, because of high recurrence rate and acquired resistance to targeting drugs such as gefitinib. Here we uncover a critical MTHFD2 enzyme-mediated purine synthesis pathway in mitochondria in poor prognostic lung cancer. Expression of MTHFD2 was induced by epidermal growth factor (EGF) stimulation. It was overexpressed in gefitinib-resistant cancer cells and high-grade tumor tissues. Knockdown of MTHFD2 significantly decreased not only in vitro and in vivo cell growth but also tumor sphere formation and tumor initiating activity, properties of cancer stem-like cells. Integrated analysis of metabolome and transcriptome of MTHFD2 knocked-down cells revealed significant accumulation of the nucleotide intermediates before MTHFD2-mediated one carbon transfer and marked deficiency of purine nucleotides required for cell growth. Thus we provide evidence that MTHFD2 pathway is critical for growth of both cancer cells and cancer stem-like cells as an Achilles heel to eradicate tumors in poor prognostic lung cancer.
2019-07-02 | GSE84007 | GEO
Project description:Subcellular compartmentalization of metabolic enzymes may elicit specific cellular functions by establishing a unique metabolic environment. Indeed, the nuclear translocation of certain metabolic enzymes is required for epigenetic regulation and gene expression control. Here, we reveal that, in cancer cells, the mitochondrial enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) localizes in the nucleus during the G2-M phase of the cell cycle to secure mitosis progression. Nuclear MTHFD2 interacts with proteins involved in mitosis regulation and centromere stability, including the methyltransferases KMT5A and DNMT3B. Loss of MTHFD2 induces centromere overexpression and severe methylation defects, and impedes correct mitosis completion. As a consequence, MTHFD2 deficient cells accumulate chromosomal aberrations arising from chromosome congression and segregation defects. Blocking the catalytic nuclear function of MTHFD2 recapitulates the phenotype observed in MTHFD2 deficient cells, attributing to nuclear MTHFD2 an enzymatic active role in controlling mitosis. Our discovery uncovers a nuclear moonlighting role for the cancer target MTHFD2, and emphasizes that cancer metabolism rewiring may encompass the relocation of metabolic enzymes to alternative subcellular compartments.
2024-07-26 | GSE230750 | GEO
Project description:We performed transcriptome analysis of Human Aortic Endothelial Cells after siRNA mediated knockdown of MTHFD2. We identified MTHFD2 as a key driver for a gene cluster which integrates mitochondrial one-carbon metabolism, serine synthesizing enzymes as well as common amino acid and ER stress response genes.
2018-06-19 | GSE100261 | GEO
Project description:Purpose: Identify new targets in acute myeloid leukemia (AML). Methods: MOLM-14 cells were transduced with lentivirus encoding shRNAs targeting MTHFD2 (shMTHFD2 hairpin TRCN0000036553, denoted M5) and control (LacZ, shControl TRCN0000072231). RNA from 6 samples, biological duplicates (LacZ1, LacZ2; M5-1, M5-2) and a technical replicate (LacZ3, M5-3) were sequenced as 50+50 bp paired-end reads using Illumina TruSeq strand specific library. The pool of six samples was sequenced on two lanes of an Illumina HiSeq, generating 101bp paired end reads. The software package RSEM (Li et al., 2001) was run using Bowtie (version 1.0.0) to align the reads that passed quality filters to the hg19 GENCODE version 17 (http://www.gencodegenes.org/releases/17.html) transcriptome and to quantify transcript abundance at isoform and gene level. Results: MTHFD2 suppression induces AML differentiation. There was upregulation of well-validated myeloid differentiation genes and gene sets consistent with myeloid maturation. Conclusion: Our study supports the therapeutic targeting of MTHFD2 in AML.
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