bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2021‒12‒05
three papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Mol Cell. 2021 Nov 22. pii: S1097-2765(21)00956-4. [Epub ahead of print]
      Quantitative subcellular metabolomic measurements can explain the roles of metabolites in cellular processes but are subject to multiple confounding factors. We developed stable isotope labeling of essential nutrients in cell culture-subcellular fractionation (SILEC-SF), which uses isotope-labeled internal standard controls that are present throughout fractionation and processing to quantify acyl-coenzyme A (acyl-CoA) thioesters in subcellular compartments by liquid chromatography-mass spectrometry. We tested SILEC-SF in a range of sample types and examined the compartmentalized responses to oxygen tension, cellular differentiation, and nutrient availability. Application of SILEC-SF to the challenging analysis of the nuclear compartment revealed a nuclear acyl-CoA profile distinct from that of the cytosol, with notable nuclear enrichment of propionyl-CoA. Using isotope tracing, we identified the branched chain amino acid isoleucine as a major metabolic source of nuclear propionyl-CoA and histone propionylation, thus revealing a new mechanism of crosstalk between metabolism and the epigenome.
    Keywords:  acyl-CoA; branched chain amino acids; histone; internal standard; isoleucine; matrix effects; metabolomics; mitochondria; nucleus; propionylation; subcellular
  2. Rejuvenation Res. 2021 Nov 30.
      Stem cell dysfunction is a hallmark of aging. Much recent work suggests that epigenetic changes play a critical role in the loss of stem cell function with age. However, the underlying mechanisms require elucidation. A recent report describes a process by which mild mitochondrial stress associated with aging causes lysosomal mediated decreases in CiC, the mitochondrial citrate transporter, in bone-derived mesenchymal stem cells (MSCs). This, in turn, results in a deficit of acetyl-CoA in the nucleus and hypoacetylation of histones. The altered epigenome results in skewered stem cell differentiation favoring adipogenesis and disfavoring osteogenesis, which is problematic given the role the MSCs play in maintaining the integrity of bone tissue. Restoration of nuclear acetyl-CoA by either ectopic expression of CiC or acetate supplementation of MSCs in culture rejuvenates the MSC, restoring the potential to efficiently differentiate along the osteogenic lineage. Citrate, which has recently been reported to extend lifespan in Drosophila, chemically incorporates acetyl-CoA and may prove useful to restore cytoplasmic and nuclear acetyl-CoA levels. The general applicability of the CiC defect in old cells, particularly stem cells, should be established.
  3. Cancer Discov. 2021 Nov 30. pii: candisc.1077.2021. [Epub ahead of print]
      Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple a-ketoglutarate-dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate-mediated mechanisms - suppression of CD8+ T cell activity and tumor cell-autonomous inactivation of TET2 DNA demethylase. Pharmacological mIDH1 inhibition stimulates CD8+ T cell recruitment and IFN-y expression and promotes TET2-dependent induction of IFN-y response genes in tumor cells. CD8+ T cell depletion or tumor cell-specific ablation of TET2 or Interferon-gamma receptor 1 causes treatment resistance. Whereas immune checkpoint activation limits mIDH1 inhibitor efficacy, CTLA4 blockade overcomes immunosuppression, providing therapeutic synergy. The findings in this mouse model of cholangiocarcinoma demonstrate that immune function and the IFN-y-TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for harnessing these inhibitors therapeutically.