bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2024–12–15
seven papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine
  1. Nutrient-driven histone code determines exhausted CD8+ T cell fates.
  2. Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis.
  3. Crosstalk between metabolic and epigenetic modifications during cell carcinogenesis.
  4. ATP citrate lyase drives vascular remodeling in systemic and pulmonary vascular diseases through metabolic and epigenetic changes.
  5. Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma.
  6. Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity.
  7. D-sodium lactate promotes the activation of NF-κB signaling pathway induced by lipopolysaccharide via histone lactylation in bovine mammary epithelial cells.
  1. Science. 2024 Dec 12. eadj3020
    Nutrient-driven histone code determines exhausted CD8+ T cell fates.
    Shixin Ma, Michael S Dahabieh, Thomas H Mann, Steven Zhao, Bryan McDonald, Won-Suk Song, H Kay Chung, Yagmur Farsakoglu, Lizmarie Garcia-Rivera, Filipe Araujo Hoffmann, Shihao Xu, Victor Y Du, Dan Chen, Jesse Furgiuele, Michael LaPorta, Emily Jacobs, Lisa M DeCamp, Brandon M Oswald, Ryan D Sheldon, Abigail E Ellis, Longwei Liu, Peixiang He, Yingxiao Wang, Cholsoon Jang, Russell G Jones, Susan M Kaech.
      Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing their protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. We showed that TEX cells shifted from acetate to citrate metabolism by downregulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increased citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions, at TEX signature-genes while reducing acetate-dependent histone acetylation, dependent on p300-ACSS2 complexes, at effector and memory T cell genes. Nuclear ACSS2 overexpression or ACLY inhibition prevented TEX differentiation and enhanced tumor-specific T cell responses. These findings unveiled a nutrient-instructed histone code governing CD8+ T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies.
    DOI:  https://doi.org/10.1126/science.adj3020
  2. Cell Metab. 2024 Dec 04. pii: S1550-4131(24)00451-0. [Epub ahead of print]
    Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis.
    Ruilong Liu, Xuelian Ren, Yae Eun Park, Huixu Feng, Xinlei Sheng, Xiaohan Song, Roya AminiTabrizi, Hardik Shah, Lingting Li, Yu Zhang, Kalil G Abdullah, Sarah Dubois-Coyne, Hening Lin, Philip A Cole, Ralph J DeBerardinis, Samuel K McBrayer, He Huang, Yingming Zhao.
      Histone lysine lactylation is a physiologically and pathologically relevant epigenetic pathway that can be stimulated by the Warburg effect-associated L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-coenzyme A (CoA) and how this process is regulated remains unknown. Here, we report the identification of guanosine triphosphate (GTP)-specific SCS (GTPSCS) as a lactyl-CoA synthetase in the nucleus. The mechanism was elucidated through the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to elevate histone lactylation but not succinylation. This process depends on a nuclear localization signal in the GTPSCS G1 subunit and acetylation at G2 subunit residue K73, which mediates the interaction with p300. GTPSCS/p300 collaboration synergistically regulates histone H3K18la and GDF15 expression, promoting glioma proliferation and radioresistance. GTPSCS represents the inaugural enzyme to catalyze lactyl-CoA synthesis for epigenetic histone lactylation and regulate oncogenic gene expression in glioma.
    Keywords:  GDF15; histone marks; hypoxia; lactyl-CoA; lactyl-CoA synthetase; lactylation; p300; succinyl-CoA synthetase; the Warburg effect; tumorigenesis
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.005
  3. iScience. 2024 Dec 20. 27(12): 111359
    Crosstalk between metabolic and epigenetic modifications during cell carcinogenesis.
    Yue Gao, Siyu Zhang, Xianhong Zhang, Yitian Du, Ting Ni, Shuailin Hao.
      Genetic mutations arising from various internal and external factors drive cells to become cancerous. Cancerous cells undergo numerous changes, including metabolic reprogramming and epigenetic modifications, to support their abnormal proliferation. This metabolic reprogramming leads to the altered expression of many metabolic enzymes and the accumulation of metabolites. Recent studies have shown that these enzymes and metabolites can serve as substrates or cofactors for chromatin-modifying enzymes, thereby participating in epigenetic modifications and promoting carcinogenesis. Additionally, epigenetic modifications play a role in the metabolic reprogramming and immune evasion of cancer cells, influencing cancer progression. This review focuses on the origins of cancer, particularly the metabolic reprogramming of cancer cells and changes in epigenetic modifications. We discuss how metabolites in cancer cells contribute to epigenetic remodeling, including lactylation, acetylation, succinylation, and crotonylation. Finally, we review the impact of epigenetic modifications on tumor immunity and the latest advancements in cancer therapies targeting these modifications.
    Keywords:  Epigenetics; Molecular genetics
    DOI:  https://doi.org/10.1016/j.isci.2024.111359
  4. Sci Transl Med. 2024 Dec 11. 16(777): eado7824
    ATP citrate lyase drives vascular remodeling in systemic and pulmonary vascular diseases through metabolic and epigenetic changes.
    Yann Grobs, Charlotte Romanet, Sarah-Eve Lemay, Alice Bourgeois, Pierre Voisine, Charlie Theberge, Melanie Sauvaget, Sandra Breuils-Bonnet, Sandra Martineau, Reem El Kabbout, Chanil Valasarajan, Prakash Chelladurai, Andreanne Pelletier, Manon Mougin, Elizabeth Dumais, Jean Perron, Nicolas Flamand, François Potus, Steeve Provencher, Soni Savai Pullamsetti, Olivier Boucherat, Sebastien Bonnet.
      ATP citrate lyase (ACLY), a crucial enzyme in de novo lipid synthesis and histone acetylation, plays a key role in regulating vascular smooth muscle cell (VSMC) proliferation and survival. We found that human coronary and pulmonary artery tissues had up-regulated ACLY expression during vascular remodeling in coronary artery disease and pulmonary arterial hypertension. Pharmacological and genetic inhibition of ACLY in human primary cultured VSMCs isolated from the coronary arteries of patients with coronary artery diseases and from the distal pulmonary arteries of patients with pulmonary arterial hypertension resulted in reduced cellular proliferation and migration and increased susceptibility to apoptosis. These cellular changes were linked to diminished glycolysis, reduced lipid synthesis, impairment in general control nonrepressed protein 5 (GCN5)-dependent histone acetylation and suppression of the transcription factor FOXM1. In vivo studies using a pharmacological inhibitor and VSMC-specific Acly knockout mice showed that ACLY inhibition alleviated vascular remodeling. ACLY inhibition alleviated remodeling in carotid injury and ligation models in rodents and attenuated pulmonary arterial hypertension in Sugen/hypoxia rat and mouse models. Moreover, ACLY inhibition showed improvements in vascular remodeling in human ex vivo models, which included cultured human coronary artery and saphenous vein rings as well as precision-cut lung slices. Our results propose ACLY as a novel therapeutic target for treating complex vascular diseases, offering promising avenues for future clinical intervention.
    DOI:  https://doi.org/10.1126/scitranslmed.ado7824
  5. bioRxiv. 2024 Nov 21. pii: 2024.11.20.624542. [Epub ahead of print]
    Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma.
    Navyateja Korimerla, Baharan Meghdadi, Isra Haq, Kari Wilder-Romans, Jie Xu, Nicole Becker, Ziqing Zhu, Peter Kalev, Nathan Qi, Charles Evans, Maureen Kachman, Zitong Zhao, Angelica Lin, Andrew J Scott, Alexandra O'Brien, Ayesha Kothari, Peter Sajjakulnukit, Li Zhang, Sravya Palavalasa, Erik R Peterson, Marc L Hyer, Katya Marjon, Taryn Sleger, Meredith A Morgan, Costas A Lyssiotis, Everett M Stone, Sean P Ferris, Theodore S Lawrence, Deepak Nagrath, Weihua Zhou, Daniel R Wahl.
      Glioblastoma (GBM) is uniformly lethal due to profound treatment resistance. Altered cellular metabolism is a key mediator of GBM treatment resistance. Uptake of the essential sulfur-containing amino acid methionine is drastically elevated in GBMs compared to normal cells, however, it is not known how this methionine is utilized or whether it relates to GBM treatment resistance. Here, we find that radiation acutely increases the levels of methionine-related metabolites in a variety of treatment-resistant GBM models. Stable isotope tracing studies further revealed that radiation acutely activates methionine to S-adenosyl methionine (SAM) conversion through an active signaling event mediated by the kinases of the DNA damage response. In vivo tumor SAM synthesis increases after radiation, while normal brain SAM production remains unchanged, indicating a tumor- specific metabolic alteration to radiation. Pharmacological and dietary strategies to block methionine to SAM conversion slowed DNA damage response and increased cell death following radiation in vitro. Mechanistically, these effects are due to depletion of DNA repair proteins and are reversed by SAM supplementation. These effects are selective to GBMs lacking the methionine salvage enzyme methylthioadenosine phosphorylase. Pharmacological inhibition of SAM synthesis hindered tumor growth in flank and orthotopic in vivo GBM models when combined with radiation. By contrast, methionine depletion does not reduce tumor SAM levels and fails to radiosensitize intracranial models, indicating depleting SAM, as opposed to simply lowering methionine, is critical for hindering tumor growth in intracranial models of GBM. These results highlight a new signaling link between DNA damage and SAM synthesis and define the metabolic fates of methionine in GBM in vivo . Inhibiting radiation-induced SAM synthesis slows DNA repair and augments radiation efficacy in GBM. Using MAT2A inhibitors to deplete SAM may selectively overcome treatment resistance in GBMs with defective methionine salvage while sparing normal brain.
    DOI:  https://doi.org/10.1101/2024.11.20.624542
  6. Cancer Cell. 2024 Dec 03. pii: S1535-6108(24)00438-0. [Epub ahead of print]
    Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity.
    Yajing Qiu, Yapeng Su, Ermei Xie, Hongcheng Cheng, Jing Du, Yue Xu, Xiaoli Pan, Zhe Wang, Daniel G Chen, Hong Zhu, Philip D Greenberg, Guideng Li.
      Cellular metabolic status profoundly influences T cell differentiation, persistence, and anti-tumor efficacy. Our single-cell metabolic analyses of T cells reveal that diminished mannose metabolism is a prominent feature of T cell dysfunction. Conversely, experimental augmentation/restoration of mannose metabolism in adoptively transferred T cells via D-mannose supplementation enhances anti-tumor activity and restricts exhaustion differentiation both in vitro and in vivo. Mechanistically, D-mannose treatment induces intracellular metabolic programming and increases the O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of β-catenin, which preserves Tcf7 expression and epigenetic stemness, thereby promoting stem-like programs in T cells. Furthermore, in vitro expansion with D-mannose supplementation yields T cell products for adoptive therapy with stemness characteristics, even after extensive long-term expansion, that exhibits enhanced anti-tumor efficacy. These findings reveal cell-intrinsic mannose metabolism as a physiological regulator of CD8+ T cell fate, decoupling proliferation/expansion from differentiation, and underscoring the therapeutic potential of mannose modulation in cancer immunotherapy.
    DOI:  https://doi.org/10.1016/j.ccell.2024.11.003
  7. Microb Pathog. 2024 Dec 09. pii: S0882-4010(24)00665-X. [Epub ahead of print]199 107198
    D-sodium lactate promotes the activation of NF-κB signaling pathway induced by lipopolysaccharide via histone lactylation in bovine mammary epithelial cells.
    Nana Ma, Lairong Wang, Meijuan Meng, Yan Wang, Ran Huo, Guangjun Chang, Xiangzhen Shen.
      Lactate is a glycolytic end product that is further metabolized as an energy source. This end product has been associated with certain diseases, including sepsis and tumors, and it can regulate the transition of macrophages to an anti-inflammatory state. This study aimed to explore the effects of lactate on the inflammatory responses of mammary gland epithelial cells, which constitute the first line of defense against pathogens in mammary glands. Bovine mammary epithelial cells (BMECs) were challenged with lipopolysaccharide (LPS) in the presence or absence of D-sodium lactate (D-nala). LPS exposure increased the concentration of lactate both inside and outside the cells. Further, inhibiting glycolysis diminished the LPS-induced production of proinflammatory cytokines. Treatment with LPS, exogenous D-nala, and their combination upregulated the expression levels of MCT1, increased the intracellular levels of lactate and histone H3 lysine 18 lactylation (H3K18la), and activated the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling pathway. The lactylation of H3K18 was mediated by p300/CBP. The p300/CBP inhibitor C646 decreased the level of H3K18la, reversing the activation of the NF-κB signaling pathway and release of proinflammatory cytokines. Therefore, LPS increased the intracellular level of lactate by upregulating MCT1 and glycolysis. D-nala exacerbated the LPS-induced inflammatory responses in BMECs. Moreover, intracellular lactate enhanced the activation of the NF-κB signaling pathway through the p300/CBP-mediated lactylation of H3K18. Thus, the findings of this study expand our understanding of lactate function in immune regulation.
    Keywords:  Bovine mammary epithelial cells; D-sodium lactate; Histone lactylation; NF-Kappa B; p300/CBP
    DOI:  https://doi.org/10.1016/j.micpath.2024.107198
This page is being maintained by Thomas Krichel. It was last updated on 2025‒12‒28 at 10:35.