bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2024–09–15
eight papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine
  1. Endothelial metabolic control of insulin sensitivity through resident macrophages.
  2. Control of epigenomic landscape and development of fetal male germ cells through L-serine metabolism.
  3. O-GlcNAcylation mediates Wnt-stimulated bone formation by rewiring aerobic glycolysis.
  4. Acetate to the rescue: Acetyl-CoA facilitates placental development.
  5. Acetate enhances spatial memory in females via sex- and brain region-specific epigenetic and transcriptional remodeling.
  6. Maternal high-fat diet alters Tet-mediated epigenetic regulation during heart development.
  7. A metabolic crosstalk between liposarcoma and muscle sustains tumor growth.
  8. Spatial single-cell isotope tracing reveals heterogeneity of de novo fatty acid synthesis in cancer.
  1. Cell Metab. 2024 Sep 08. pii: S1550-4131(24)00335-8. [Epub ahead of print]
    Endothelial metabolic control of insulin sensitivity through resident macrophages.
    Jing Zhang, Kim Anker Sjøberg, Songlin Gong, Tongtong Wang, Fengqi Li, Andrew Kuo, Stephan Durot, Adam Majcher, Raphaela Ardicoglu, Thibaut Desgeorges, Charlotte Greta Mann, Ines Soro Arnáiz, Gillian Fitzgerald, Paola Gilardoni, E Dale Abel, Shigeyuki Kon, Danyvid Olivares-Villagómez, Nicola Zamboni, Christian Wolfrum, Thorsten Hornemann, Raphael Morscher, Nathalie Tisch, Bart Ghesquière, Manfred Kopf, Erik A Richter, Katrien De Bock.
      Endothelial cells (ECs) not only form passive blood conduits but actively contribute to nutrient transport and organ homeostasis. The role of ECs in glucose homeostasis is, however, poorly understood. Here, we show that, in skeletal muscle, endothelial glucose transporter 1 (Glut1/Slc2a1) controls glucose uptake via vascular metabolic control of muscle-resident macrophages without affecting transendothelial glucose transport. Lowering endothelial Glut1 via genetic depletion (Glut1ΔEC) or upon a short-term high-fat diet increased angiocrine osteopontin (OPN/Spp1) secretion. This promoted resident muscle macrophage activation and proliferation, which impaired muscle insulin sensitivity. Consequently, co-deleting Spp1 from ECs prevented macrophage accumulation and improved insulin sensitivity in Glut1ΔEC mice. Mechanistically, Glut1-dependent endothelial glucose metabolic rewiring increased OPN in a serine metabolism-dependent fashion. Our data illustrate how the glycolytic endothelium creates a microenvironment that controls resident muscle macrophage phenotype and function and directly links resident muscle macrophages to the maintenance of muscle glucose homeostasis.
    Keywords:  GLUT1; endothelial cells; endothelial metabolism; inflammation; insulin sensitivity; osteopontin; resident macrophages; serine; skeletal muscle; vasculature
    DOI:  https://doi.org/10.1016/j.cmet.2024.08.008
  2. iScience. 2024 Sep 20. 27(9): 110702
    Control of epigenomic landscape and development of fetal male germ cells through L-serine metabolism.
    Yohei Hayashi, Jintaro Kaneko, Yumi Ito-Matsuoka, Asuka Takehara, Mayuka Funakoshi, So Maezawa, Kenjiro Shirane, Shigeki Furuya, Yasuhisa Matsui.
      Sex-specific metabolic characteristics emerge in the mouse germ line after reaching the genital ridges around embryonic day 10.5, coinciding with sexual differentiation. However, the impact of such metabolic characteristics on germ cell development remains unclear. In this study, we observed the specific upregulation in male fetal germ cells of D-3-phosphoglycerate dehydrogenase (PHGDH), the primary enzyme in the serine-glycine-one-carbon metabolism, along with an increase in a downstream metabolite, S-adenosylmethionine (SAM), crucial for protein and nucleic acid methylation. Inhibiting PHGDH in fetal testes resulted in reduced SAM levels in germ cells, accompanied by increases in the number of mouse vasa homolog (MVH/VASA)-positive germ cells and the promyelocytic leukemia zinc finger (PLZF)-positive undifferentiated spermatogonia ratio. Furthermore, PHGDH inhibition led to a decrease in the methylation of histone H3 and DNA, resulting in aberrations in gene expression profiles. In summary, our findings underscore the significant role of certain metabolic mechanisms in the development of male germ cells.
    Keywords:  Cellular physiology; Developmental biology; Epigenetics
    DOI:  https://doi.org/10.1016/j.isci.2024.110702
  3. EMBO Rep. 2024 Sep 10.
    O-GlcNAcylation mediates Wnt-stimulated bone formation by rewiring aerobic glycolysis.
    Chengjia You, Fangyuan Shen, Puying Yang, Jingyao Cui, Qiaoyue Ren, Moyu Liu, Yujie Hu, Boer Li, Ling Ye, Yu Shi.
      Wnt signaling is an important target for anabolic therapies in osteoporosis. A sclerostin-neutralizing antibody (Scl-Ab), that blocks the Wnt signaling inhibitor (sclerostin), has been shown to promote bone mass in animal models and clinical studies. However, the cellular mechanisms by which Wnt signaling promotes osteogenesis remain to be further investigated. O-GlcNAcylation, a dynamic post-translational modification of proteins, controls multiple critical biological processes including transcription, translation, and cell fate determination. Here, we report that Wnt3a either induces O-GlcNAcylation rapidly via the Ca2+-PKA-Gfat1 axis, or increases it in a Wnt-β-catenin-dependent manner following prolonged stimulation. Importantly, we find O-GlcNAcylation indispensable for osteoblastogenesis both in vivo and in vitro. Genetic ablation of O-GlcNAcylation in the osteoblast-lineage diminishes bone formation and delays bone fracture healing in response to Wnt stimulation in vivo. Mechanistically, Wnt3a induces O-GlcNAcylation at Serine 174 of PDK1 to stabilize the protein, resulting in increased glycolysis and osteogenesis. These findings highlight O-GlcNAcylation as an important mechanism regulating Wnt-induced glucose metabolism and bone anabolism.
    Keywords:  Bone Formation; Fracture Healing; Glucose Metabolism; O-GlcNAcylation; Wnt
    DOI:  https://doi.org/10.1038/s44319-024-00237-z
  4. Cell Stem Cell. 2024 Sep 05. pii: S1934-5909(24)00289-3. [Epub ahead of print]31(9): 1241-1243
    Acetate to the rescue: Acetyl-CoA facilitates placental development.
    Joseph Festa, Sophie Trefely.
      While the placenta regulates nutritional exchange between mother and fetus, Yu et al. reveal that human placental development is itself nutrient-sensitive. They elucidate entwined metabolic and epigenetic transitions driving syncytialization and pinpoint a requirement for the metabolite acetyl-CoA, which is sensitive to glucose metabolism.
    DOI:  https://doi.org/10.1016/j.stem.2024.08.003
  5. bioRxiv. 2024 Aug 27. pii: 2024.08.26.609729. [Epub ahead of print]
    Acetate enhances spatial memory in females via sex- and brain region-specific epigenetic and transcriptional remodeling.
    Erica M Periandri, Kala M Dodson, Francisca N Vitorino, Benjamin A Garcia, Karl M Glastad, Gabor Egervari.
      Metabolic control of chromatin and gene expression is emerging as a key, but largely unexplored aspect of gene regulation. In the brain, metabolic-epigenetic interactions can influence critical neuronal functions. Here, we use a combination of behavioral, proteomic and genomic approaches to demonstrate that the intermediary metabolite acetate enhances memory in a brain region- and sex-specific manner. We show that acetate facilitates the formation of dorsal hippocampus-dependent spatial memories in female but not in male mice, while having no effect on cortex-dependent non-spatial memories in either sex. Acetate-enhanced spatial memory is driven by increased acetylation of histone variant H2A.Z, and upregulation of genes implicated in spatial learning in the dorsal hippocampus of female mice. In line with the sex-specific behavioral outcomes, the effect of acetate on dorsal hippocampal histone modifications and gene expression shows marked differences between the sexes during critical windows of memory formation (consolidation and recall). Overall, our findings elucidate a novel role for acetate, a ubiquitous and abundant metabolite, in regulating dorsal hippocampal chromatin, gene expression and learning, and outline acetate exposure as a promising new approach to enhance memory formation.
    DOI:  https://doi.org/10.1101/2024.08.26.609729
  6. iScience. 2024 Sep 20. 27(9): 110631
    Maternal high-fat diet alters Tet-mediated epigenetic regulation during heart development.
    Yuhan Yang, Logan Rivera, Shaohai Fang, Maryn Cavalier, Ashley Suris, Yubin Zhou, Yun Huang.
      Imbalanced dietary intake, such as a high-fat diet (HFD) during pregnancy, has been associated with adverse offspring outcomes. Metabolic stress from imbalanced food intake alters the function of epigenetic regulators, resulting in abnormal transcriptional outputs in embryos to cause congenital disorders. We report herein that maternal HFD exposure causes metabolic changes in pregnant mice and non-compaction cardiomyopathy (NCC) in E15.5 embryos, accompanied by decreased 5-hydroxymethylcytosine (5hmC) levels and altered chromatin accessibility in embryonic heart tissues. Remarkably, maternal vitamin C supplementation mitigates these detrimental effects, likely by restoring iron, a cofactor for Tet enzymes, in a reduced state. Using a genetic approach, we further demonstrated that the cardioprotective benefits of vitamin C under HFD conditions are attributable to enhanced Tet activity. Our results highlight an interaction between maternal diet, specifically HFD or vitamin C, and epigenetic modifications during early heart development, emphasizing the importance of balanced maternal nutrition for healthy embryonic development.
    Keywords:  Developmental biology; Diet; Epigenetics; Model organism; Pregnancy
    DOI:  https://doi.org/10.1016/j.isci.2024.110631
  7. Nat Commun. 2024 Sep 12. 15(1): 7940
    A metabolic crosstalk between liposarcoma and muscle sustains tumor growth.
    Gabrielle Manteaux, Alix Amsel, Blanche Riquier-Morcant, Jaime Prieto Romero, Laurie Gayte, Benjamin Fourneaux, Marion Larroque, Nadège Gruel, Chloé Quignot, Gaelle Perot, Solenn Jacq, Madi Y Cisse, Pascal Pomiès, Coralie Sengenes, Frédéric Chibon, Maud Heuillet, Floriant Bellvert, Sarah Watson, Sebastien Carrere, Nelly Firmin, Romain Riscal, Laetitia K Linares.
      Dedifferentiated and Well-differentiated liposarcoma are characterized by a systematic amplification of the Murine Double Minute 2 (MDM2) oncogene. We demonstrate that p53-independent metabolic functions of chromatin-bound MDM2 are exacerbated in liposarcoma and mediate an addiction to serine metabolism to sustain tumor growth. However, the origin of exogenous serine remains unclear. Here, we show that elevated serine levels in mice harboring liposarcoma-patient derived xenograft, released by distant muscle is essential for liposarcoma cell survival. Repressing interleukine-6 expression, or treating liposarcoma cells with Food and Drugs Administration (FDA) approved anti-interleukine-6 monoclonal antibody, decreases de novo serine synthesis in muscle, impairs proliferation, and increases cell death in vitro and in vivo. This work reveals a metabolic crosstalk between muscle and liposarcoma tumor and identifies anti-interleukine-6 as a plausible treatment for liposarcoma patients.
    DOI:  https://doi.org/10.1038/s41467-024-51827-3
  8. Nat Metab. 2024 Sep 09.
    Spatial single-cell isotope tracing reveals heterogeneity of de novo fatty acid synthesis in cancer.
    Elena Buglakova, Måns Ekelöf, Michaela Schwaiger-Haber, Lisa Schlicker, Martijn R Molenaar, Mohammed Shahraz, Lachlan Stuart, Andreas Eisenbarth, Volker Hilsenstein, Gary J Patti, Almut Schulze, Marteinn T Snaebjornsson, Theodore Alexandrov.
      While heterogeneity is a key feature of cancer, understanding metabolic heterogeneity at the single-cell level remains a challenge. Here we present 13C-SpaceM, a method for spatial single-cell isotope tracing that extends the previously published SpaceM method with detection of 13C6-glucose-derived carbons in esterified fatty acids. We validated 13C-SpaceM on spatially heterogeneous models using liver cancer cells subjected to either normoxia-hypoxia or ATP citrate lyase depletion. This revealed substantial single-cell heterogeneity in labelling of the lipogenic acetyl-CoA pool and in relative fatty acid uptake versus synthesis hidden in bulk analyses. Analysing tumour-bearing brain tissue from mice fed a 13C6-glucose-containing diet, we found higher glucose-dependent synthesis of saturated fatty acids and increased elongation of essential fatty acids in tumours compared with healthy brains. Furthermore, our analysis uncovered spatial heterogeneity in lipogenic acetyl-CoA pool labelling in tumours. Our method enhances spatial probing of metabolic activities in single cells and tissues, providing insights into fatty acid metabolism in homoeostasis and disease.
    DOI:  https://doi.org/10.1038/s42255-024-01118-4
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