bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2024–01–07
seven papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine
  1. Mitochondrial isocitrate dehydrogenase impedes CAR T cell function by restraining antioxidant metabolism and histone acetylation.
  2. Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors.
  3. ROS-induced metabolic reprogramming to one-carbon metabolism and S-adenosylmethionine-mediated epigenetic modification in IL-10-producing B cells for the resolution of pneumonia.
  4. Histone lactylation couples cellular metabolism with developmental gene regulatory networks.
  5. NME4 mediates metabolic reprogramming and promotes nonalcoholic fatty liver disease progression.
  6. ATP citrate lyase (ACLY)-dependent immunometabolism in mucosal T cells drives experimental colitis in vivo.
  7. Specific regulation of epigenome landscape by metabolic enzymes and metabolites.
  1. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00461-8. [Epub ahead of print]36(1): 176-192.e10
    Mitochondrial isocitrate dehydrogenase impedes CAR T cell function by restraining antioxidant metabolism and histone acetylation.
    Xiaohui Si, Mi Shao, Xinyi Teng, Yue Huang, Ye Meng, Longyuan Wu, Jieping Wei, Lianxuan Liu, Tianning Gu, Junzhe Song, Ruirui Jing, Xingyuan Zhai, Xin Guo, Delin Kong, Xiujian Wang, Bohan Cai, Ying Shen, Zhaoru Zhang, Dongrui Wang, Yongxian Hu, Pengxu Qian, Gang Xiao, He Huang.
      The efficacy of chimeric antigen receptor (CAR) T cell therapy is hampered by relapse in hematologic malignancies and by hyporesponsiveness in solid tumors. Long-lived memory CAR T cells are critical for improving tumor clearance and long-term protection. However, during rapid ex vivo expansion or in vivo tumor eradication, metabolic shifts and inhibitory signals lead to terminal differentiation and exhaustion of CAR T cells. Through a mitochondria-related compound screening, we find that the FDA-approved isocitrate dehydrogenase 2 (IDH2) inhibitor enasidenib enhances memory CAR T cell formation and sustains anti-leukemic cytotoxicity in vivo. Mechanistically, IDH2 impedes metabolic fitness of CAR T cells by restraining glucose utilization via the pentose phosphate pathway, which alleviates oxidative stress, particularly in nutrient-restricted conditions. In addition, IDH2 limits cytosolic acetyl-CoA levels to prevent histone acetylation that promotes memory cell formation. In combination with pharmacological IDH2 inhibition, CAR T cell therapy is demonstrated to have superior efficacy in a pre-clinical model.
    Keywords:  chimeric antigen receptor T cell; enasidenib; exhaustion; histone acetylation; isocitrate dehydrogenase 2; memory T cell formation; nutrient-restricted conditions; pentose phosphate pathway
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.010
  2. Cell Rep. 2023 Dec 30. pii: S2211-1247(23)01640-6. [Epub ahead of print]43(1): 113629
    Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors.
    Dimitris Karagiannis, Warren Wu, Albert Li, Makiko Hayashi, Xiao Chen, Michaela Yip, Vaibhav Mangipudy, Xinjing Xu, Francisco J Sánchez-Rivera, Yadira M Soto-Feliciano, Jiangbin Ye, Thales Papagiannakopoulos, Chao Lu.
      The interplay between metabolism and chromatin signaling is implicated in cancer progression. However, whether and how metabolic reprogramming in tumors generates chromatin vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor aberrant activation of the NRF2 antioxidant pathway, which drives aggressive and chemo-resistant disease. Using a chromatin-focused CRISPR screen, we report that NRF2 activation sensitizes LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDACs). This association is observed across cultured cells, mouse models, and patient-derived xenografts. Integrative epigenomic, transcriptomic, and metabolomic analysis demonstrates that HDAC inhibition causes widespread redistribution of H4ac and its reader protein, which transcriptionally downregulates metabolic enzymes. This results in reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest NRF2 activation as a potential biomarker for effective repurposing of HDAC inhibitors to treat solid tumors.
    Keywords:  CP: Cancer; HDAC inhibitors; NRF2 pathway; cancer epigenetics; cancer metabolism; cancer targeted therapy; epigenetic reprogramming; lung cancer
    DOI:  https://doi.org/10.1016/j.celrep.2023.113629
  3. Cell Mol Immunol. 2024 Jan 04.
    ROS-induced metabolic reprogramming to one-carbon metabolism and S-adenosylmethionine-mediated epigenetic modification in IL-10-producing B cells for the resolution of pneumonia.
    Sujin Lee, Tae Jin Kim.
      
    DOI:  https://doi.org/10.1038/s41423-023-01117-7
  4. Nat Commun. 2024 Jan 02. 15(1): 90
    Histone lactylation couples cellular metabolism with developmental gene regulatory networks.
    Fjodor Merkuri, Megan Rothstein, Marcos Simoes-Costa.
      Embryonic cells exhibit diverse metabolic states. Recent studies have demonstrated that metabolic reprogramming drives changes in cell identity by affecting gene expression. However, the connection between cellular metabolism and gene expression remains poorly understood. Here we report that glycolysis-regulated histone lactylation couples the metabolic state of embryonic cells with chromatin organization and gene regulatory network (GRN) activation. We found that lactylation marks genomic regions of glycolytic embryonic tissues, like the neural crest (NC) and pre-somitic mesoderm. Histone lactylation occurs in the loci of NC genes as these cells upregulate glycolysis. This process promotes the accessibility of active enhancers and the deployment of the NC GRN. Reducing the deposition of the mark by targeting LDHA/B leads to the downregulation of NC genes and the impairment of cell migration. The deposition of lactyl-CoA on histones at NC enhancers is supported by a mechanism that involves transcription factors SOX9 and YAP/TEAD. These findings define an epigenetic mechanism that integrates cellular metabolism with the GRNs that orchestrate embryonic development.
    DOI:  https://doi.org/10.1038/s41467-023-44121-1
  5. EMBO Rep. 2023 Dec 14.
    NME4 mediates metabolic reprogramming and promotes nonalcoholic fatty liver disease progression.
    Shaofang Xie, Lei Yuan, Yue Sui, Shan Feng, Hengle Li, Xu Li.
      Nonalcoholic fatty liver disease (NAFLD) is mainly characterized by excessive fat accumulation in the liver, and it is associated with liver-related complications and adverse systemic diseases. NAFLD has become the most prevalent liver disease; however, effective therapeutic agents for NAFLD are still lacking. We combined clinical data with proteomics and metabolomics data, and found that the mitochondrial nucleoside diphosphate kinase NME4 plays a central role in mitochondrial lipid metabolism. Nme4 is markedly upregulated in mice fed with high-fat diet, and its expression is positively correlated with the level of steatosis. Hepatic deletion of Nme4 suppresses the progression of hepatic steatosis. Further studies demonstrated that NME4 interacts with several key enzymes in coenzyme A (CoA) metabolism and increases the level of acetyl-CoA and malonyl-CoA, which are the major lipid components of the liver in NAFLD. Increased level of acetyl-CoA and malonyl-CoA  lead to increased triglyceride levels and lipid accumulation in the liver. Taken together, these findings reveal that NME4 is a critical regulator of NAFLD progression and a potential therapeutic target for NAFLD.
    Keywords:  Coenzyme A Metabolism; Lipid Accumulation; NAFLD; NME4
    DOI:  https://doi.org/10.1038/s44319-023-00012-6
  6. Gut. 2024 Jan 04. pii: gutjnl-2023-330543. [Epub ahead of print]
    ATP citrate lyase (ACLY)-dependent immunometabolism in mucosal T cells drives experimental colitis in vivo.
    TRR241 IBDome Consortium
       OBJECTIVE: Mucosal T cells play a major role in inflammatory bowel disease (IBD). However, their immunometabolism during intestinal inflammation is poorly understood. Due to its impact on cellular metabolism and proinflammatory immune cell function, we here focus on the enzyme ATP citrate lyase (ACLY) in mucosal T cell immunometabolism and its relevance for IBD.
    DESIGN: ACLY expression and its immunometabolic impact on colitogenic T cell function were analysed in mucosal T cells from patients with IBD and in two experimental colitis models.
    RESULTS: ACLY was markedly expressed in colon tissue under steady-state conditions but was significantly downregulated in lamina propria mononuclear cells in experimental dextran sodium sulfate-induced colitis and in CD4+ and to a lesser extent in CD8+ T cells infiltrating the inflamed gut in patients with IBD. ACLY-deficient CD4+ T cells showed an impaired capacity to induce intestinal inflammation in a transfer colitis model as compared with wild-type T cells. Assessment of T cell immunometabolism revealed that ACLY deficiency dampened the production of IBD-relevant cytokines and impaired glycolytic ATP production but enriched metabolites involved in the biosynthesis of phospholipids and phosphatidylcholine. Interestingly, the short-chain fatty acid butyrate was identified as a potent suppressor of ACLY expression in T cells, while IL-36α and resolvin E1 induced ACLY levels. In a translational approach, in vivo administration of the butyrate prodrug tributyrin downregulated mucosal infiltration of ACLYhigh CD4+ T cells and ameliorated chronic colitis.
    CONCLUSION: ACLY controls mucosal T cell immunometabolism and experimental colitis. Therapeutic modulation of ACLY expression in T cells emerges as a novel strategy to promote the resolution of intestinal inflammation.
    Keywords:  EXPERIMENTAL COLITIS; INFLAMMATORY BOWEL DISEASE; MUCOSAL IMMUNOLOGY; T LYMPHOCYTES
    DOI:  https://doi.org/10.1136/gutjnl-2023-330543
  7. Biol Rev Camb Philos Soc. 2024 Jan 04.
    Specific regulation of epigenome landscape by metabolic enzymes and metabolites.
    Xilan Yu, Shanshan Li.
      Metabolism includes anabolism and catabolism, which play an essential role in many biological processes. Chromatin modifications are post-translational modifications of histones and nucleic acids that play important roles in regulating chromatin-associated processes such as gene transcription. There is a tight connection between metabolism and chromatin modifications. Many metabolic enzymes and metabolites coordinate cellular activities with alterations in nutrient availability by regulating gene expression through epigenetic mechanisms such as DNA methylation and histone modifications. The dysregulation of gene expression by metabolism and epigenetic modifications may lead to diseases such as diabetes and cancer. Recent studies reveal that metabolic enzymes and metabolites specifically regulate chromatin modifications, including modification types, modification residues and chromatin regions. This specific regulation has been implicated in the development of human diseases, yet the underlying mechanisms are only beginning to be uncovered. In this review, we summarise recent studies of the molecular mechanisms underlying the metabolic regulation of histone and DNA modifications and discuss how they contribute to pathogenesis. We also describe recent developments in technologies used to address the key questions in this field. We hope this will inspire further in-depth investigations of the specific regulatory mechanisms involved, and most importantly will shed lights on the development of more effective disease therapies.
    Keywords:  DNA methylation; cell fate determination; chromatin structure; epigenetic modifications; gene transcription; histone modifications; metabolism; oncogenesis
    DOI:  https://doi.org/10.1111/brv.13049
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