bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2022‒03‒27
five papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Cell Metab. 2022 Mar 15. pii: S1550-4131(22)00087-0. [Epub ahead of print]
      Metabolic reprogramming is a hallmark of activated T cells. The switch from oxidative phosphorylation to aerobic glycolysis provides energy and intermediary metabolites for the biosynthesis of macromolecules to support clonal expansion and effector function. Here, we show that glycolytic reprogramming additionally controls inflammatory gene expression via epigenetic remodeling. We found that the glucose transporter GLUT3 is essential for the effector functions of Th17 cells in models of autoimmune colitis and encephalomyelitis. At the molecular level, we show that GLUT3-dependent glucose uptake controls a metabolic-transcriptional circuit that regulates the pathogenicity of Th17 cells. Metabolomic, epigenetic, and transcriptomic analyses linked GLUT3 to mitochondrial glucose oxidation and ACLY-dependent acetyl-CoA generation as a rate-limiting step in the epigenetic regulation of inflammatory gene expression. Our findings are also important from a translational perspective because inhibiting GLUT3-dependent acetyl-CoA generation is a promising metabolic checkpoint to mitigate Th17-cell-mediated inflammatory diseases.
    Keywords:  ACLY; ATP-citrate lyase; GLUT1; GLUT3; Th17 cells; acetyl-CoA; glucose metabolism; glycolysis; histone acetylation; immunometabolism
  2. Food Chem Toxicol. 2022 Mar 18. pii: S0278-6915(22)00136-3. [Epub ahead of print] 112938
      A diet deficient in donors of methyl group such as methionine affects DNA methylation and hepatic lipid metabolism. Methionine also affects other epigenetic mechanisms such as microRNAs. We investigated the effects of methionine-supplemented or methionine-deficient diets on the expression of chromatin-modifying genes, global DNA methylation, expression and methylation of genes related to lipid metabolism, and expression of microRNAs in mice liver. We fed female Swiss albino mice a control diet (0.3% methionine), a methionine-supplemented diet (2% methionine), and a methionine-deficient diet (0% methionine) for 10 weeks. The group of genes most affected by the supplemented diet was genes with histone and DNA methyltransferases activity, while the deficient diet most altered the expression histone methyltransferases genes. Both diets altered the global DNA methylation, expression, and gene-specific methylation of the lipid metabolism gene Apoa5. Finally, both diets altered the expression of several liver homeostasis-related microRNAs, such as miR-190b-5p, miR-130b-3p, miR-376c-3p, miR-411-5p, miR-29c-3p, miR-295-3p, and miR-467d-5p, with a more significant effect of the methionine-deficient diet. The effects of improper amount of methionine in the diet on liver pathologies might involve a cooperative action of chromatin-modifying genes, which results in an aberrant pattern of global and gene-specific methylation, and microRNAs responsible for liver homeostasis.
    Keywords:  Apoa5; Chromatin-modifying genes; Lipid metabolism; Methylation; Pparg; microRNAs
  3. Cell Death Differ. 2022 Mar 24.
      Cancer cells are known for their ability to adapt variable metabolic programs depending on the availability of specific nutrients. Our previous studies have shown that uptake of fatty acids alters cellular metabolic pathways in colon cancer cells to favor fatty acid oxidation. Here, we show that fatty acids activate Drp1 to promote metabolic plasticity in cancer cells. Uptake of fatty acids (FAs) induces mitochondrial fragmentation by promoting ERK-dependent phosphorylation of Drp1 at the S616 site. This increased phosphorylation of Drp1 enhances its dimerization and interaction with Mitochondrial Fission Factor (MFF) at the mitochondria. Consequently, knockdown of Drp1 or MFF attenuates fatty acid-induced mitochondrial fission. In addition, uptake of fatty acids triggers mitophagy via a Drp1- and p62-dependent mechanism to protect mitochondrial integrity. Moreover, results from metabolic profiling analysis reveal that silencing Drp1 disrupts cellular metabolism and blocks fatty acid-induced metabolic reprograming by inhibiting fatty acid utilization. Functionally, knockdown of Drp1 decreases Wnt/β-catenin signaling by preventing fatty acid oxidation-dependent acetylation of β-catenin. As a result, Drp1 depletion inhibits the formation of tumor organoids in vitro and xenograft tumor growth in vivo. Taken together, our study identifies Drp1 as a key mediator that connects mitochondrial dynamics with fatty acid metabolism and cancer cell signaling.
  4. Nat Metab. 2022 Mar 21.
      Tumour cells utilize multiple strategies to evade the immune system, but the underlying metabolic mechanisms remain poorly understood. The pyruvate dehydrogenase (PDH) complex converts pyruvate to acetyl-coenzyme A in mitochondria, thereby linking glycolysis to the ricarboxylic acid cycle. Here we show that the PDH complex E1 subunit α (PDHE1α) is also located in the cytosol. Cytosolic PDHE1α interacts with IKKβ and protein phosphatase 1B, thereby facilitating the inhibition of the NF-κB pathway. Cytosolic PDHE1α can be phosphorylated at S327 by ERK2 and translocated into mitochondria. Decreased cytosolic PDHE1α levels restore NF-κB signalling, whereas increased mitochondrial PDHE1α levels drive α-ketoglutarate production and promote reactive oxygen species detoxification. Synergistic activation of NF-κB and reactive oxygen species detoxification promotes tumour cell survival and enhances resistance to cytotoxic lymphocytes. Consistently, low levels of PDHE1α phosphorylation are associated with poor prognosis of patients with lung cancer. Our findings show a mechanism through which phosphorylation-dependent subcellular translocation of PDHE1α promotes tumour immune evasion.
  5. Metabolites. 2022 Mar 21. pii: 267. [Epub ahead of print]12(3):
      Tumor cells detached from the extracellular matrix (ECM) undergo anoikis resistance and metabolic reprogramming to facilitate cancer cell survival and promote metastasis. During ECM detachment, cancer cells utilize genomic methylation to regulate transcriptional events. One-carbon (1C) metabolism is a well-known contributor of SAM, a global substrate for methylation reactions, especially DNA methylation. DNA methylation-mediated repression of NK cell ligands MICA and MICB during ECM detachment has been overlooked. In the current work, we quantitated the impact of ECM detachment on one-carbon metabolites, expression of 1C regulatory pathway genes, and total methylation levels. Our results showed that ECM detachment promotes the accumulation of one-carbon metabolites and induces regulatory pathway genes and total DNA methylation. Furthermore, we measured the expression of well-known targets of DNA methylation in NK cell ligands in cancer cells, namely, MICA/B, during ECM detachment and observed low expression compared to ECM-attached cancer cells. Finally, we treated the ECM-detached cancer cells with vitamin C (a global methylation inhibitor) and observed a reduction in the promoter methylation of NK cell ligands, resulting in MICA/B re-expression. Treatment with vitamin C was also found to reduce global DNA methylation levels in ECM-detached cancer cells.
    Keywords:  DNA methylation; ECM detachment; NKG2DLs; anoikis; one-carbon metabolism