bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2023‒06‒04
seven papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Cell Rep. 2023 Jun 01. pii: S2211-1247(23)00594-6. [Epub ahead of print]42(6): 112583
      Upon antigen-specific T cell receptor (TCR) engagement, human CD4+ T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming. Here, we show that the generation of extramitochondrial pyruvate is an important step for acetyl-CoA production and subsequent H3K27ac-mediated remodeling of histone acetylation. Histone modification, transcriptomic, and carbon tracing analyses of pyruvate dehydrogenase (PDH)-deficient T cells show PDH-dependent acetyl-CoA generation as a rate-limiting step during T activation. Furthermore, T cell activation results in the nuclear translocation of PDH and its association with both the p300 acetyltransferase and histone H3K27ac. These data support the tight integration of metabolic and histone-modifying enzymes, allowing metabolic reprogramming to fuel CD4+ T cell activation. Targeting this pathway may provide a therapeutic approach to specifically regulate antigen-driven T cell activation.
    Keywords:  CP: Metabolism; T cell; citrate; epigenetics; epigenome remodeling; glucose metabolism; glycolysis; histone acetylation; nuclear metabolism; pyruvate; pyruvate dehydrogenase
  2. Development. 2023 Oct 15. pii: dev199961. [Epub ahead of print]150(20):
      Diet contributes to health at all stages of life, from embryonic development to old age. Nutrients, including vitamins, amino acids, lipids and sugars, have instructive roles in directing cell fate and function, maintaining stem cell populations, tissue homeostasis and alleviating the consequences of aging. This Review highlights recent findings that illuminate how common diets and specific nutrients impact cell fate decisions in healthy and disease contexts. We also draw attention to new models, technologies and resources that help to address outstanding questions in this emerging field and may lead to dietary approaches that promote healthy development and improve disease treatments.
    Keywords:  Cell fate decision; Dietary nutrient; Metabolism; Stem cell
  3. Cancer Immunol Res. 2023 May 30. pii: CIR-22-0565. [Epub ahead of print]
      Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we investigated whether it is possible to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism whereby cancer cells suppress T-cell function by generating a metabolically unfavorable tumor microenvironment (TME). In an in silico screen, we identified ADA and PDK1 as metabolic regulators. We then showed that overexpression (OE) of these genes enhanced the cytolysis of CD19-specific chimeric-antigen receptor (CAR) T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampened this effect. ADA-OE in CAR T cells improved cancer cytolysis under high concentrations of adenosine, the ADA substrate and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics analysis of these CAR T cells revealed alterations of global gene expression and metabolic signatures in both ADA- and PDK1-engineered CAR T cells. Functional and immunological analyses demonstrated that ADA-OE increased proliferation and decreased exhaustion in CD19-specific and HER2-specific CAR T cells. ADA-OE improved tumor infiltration and clearance by HER2-specific CAR T cells in an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR T cells and reveal potential targets for improving CAR T-cell therapy.
  4. Blood. 2023 Jun 02. pii: blood.2022018159. [Epub ahead of print]
      Sickle cell disease (SCD) is a chronic hemolysis, constant oxidative stress, and systemic hypoxia condition, and undergoes significant metabolic alterations. However, little is known about the correlation between metabolic alterations and those pathophysiological symptoms. Here we report that Nrf2, a master regulator of cellular antioxidant responses, regulates the production of the metabolite L-2-hydroxyglutarate (L2HG) to mediate epigenetic histone hypermethylation for gene expression involved in metabolic, oxidative and ferroptosis stress responses in SCD. Mechanistically, Nrf2 was found to regulate the expression of L-2-hydroxyglutarate dehydrogenase (L2hgdh) to mediate L2HG production under hypoxia. Gene expression profile analysis indicates that reactive oxygen species (ROS) and ferroptosis response are the most significantly affected signaling pathways after Nrf2 ablation in SCD. Nrf2 silencing and L2HG supplementation sensitize human sickle erythroid cells to the ROS and ferroptosis stresses. The absence of Nrf2 and accumulation of L2HG significantly affect histone methylation for chromatin structure modification and reduce the assembly of transcription complexes on downstream target genes to regulate ROS and ferroptosis responses. Furthermore, pharmacological activation of Nrf2 was found to render protective effects against ROS and ferroptosis stresses in SCD mice. Our data suggest a novel mechanism by which Nrf2 regulates L2HG levels to mediate SCD severity through ROS and ferroptosis stress responses and targeting Nrf2 is a viable therapeutic strategy to ameliorate SCD symptoms.
  5. Sci Adv. 2023 Jun 02. 9(22): eadg0478
      Hemodynamic overload and dysregulation of cellular metabolism are involved in development of calcific aortic valve disease (CAVD). However, how mechanical stress relates to metabolic changes in CAVD remains unclear. Here, we show that Piezo1, a mechanosensitive ion channel, regulated glutaminase 1 (GLS1)-mediated glutaminolysis to promote osteogenic differentiation of valve interstitial cells (VICs). In vivo, two models of aortic valve stenosis were constructed by ascending aortic constriction (AAC) and direct wire injury (DWI). Inhibition of Piezo1 and GLS1 in these models respectively mitigated aortic valve lesion. In vitro, Piezo1 activation induced by Yoda1 and oscillatory stress triggered osteogenic responses in VICs, which were prevented by Piezo1 inhibition or knockdown. Mechanistically, Piezo1 activation promoted calcium-dependent Yes-associated protein (YAP) activation. YAP modulated GLS1-mediated glutaminolysis, which enhanced osteogenic differentiation through histone acetylation of runt-related transcription factor 2 (RUNX2) promoters. Together, our work provided a cross-talk between mechanotransduction and metabolism in the context of CAVD.
  6. Front Genet. 2023 ;14 1158089
      Maternal high-fat diet (HFD) during pregnancy is associated with rapid weight gain and fetal fat mass increase at an early stage. Also, HFD during pregnancy can cause the activation of proinflammatory cytokines. Maternal insulin resistance and inflammation lead to increased adipose tissue lipolysis, and also increased free fatty acid (FFA) intake during pregnancy (˃35% of energy from fat) cause a significant increase in FFA levels in the fetus. However, both maternal insulin resistance and HFD have detrimental effects on adiposity in early life. As a result of these metabolic alterations, excess fetal lipid exposure may affect fetal growth and development. On the other hand, increase in blood lipids and inflammation can adversely affect the development of the liver, adipose tissue, brain, skeletal muscle, and pancreas in the fetus, increasing the risk for metabolic disorders. In addition, maternal HFD is associated with changes in the hypothalamic regulation of body weight and energy homeostasis by altering the expression of the leptin receptor, POMC, and neuropeptide Y in the offspring, as well as altering methylation and gene expression of dopamine and opioid-related genes which cause changes in eating behavior. All these maternal metabolic and epigenetic changes may contribute to the childhood obesity epidemic through fetal metabolic programming. Dietary interventions, such as limiting dietary fat intake <35% with appropriate fatty acid intake during the gestation period are the most effective type of intervention to improve the maternal metabolic environment during pregnancy. Appropriate nutritional intake during pregnancy should be the principal goal in reducing the risks of obesity and metabolic disorders.
    Keywords:  fetal programming; high fat diet; hypothalamic programming; maternal obesity; maternal overnutiriton
  7. Mol Syst Biol. 2023 Jun 01. e11267
      While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential for the resolution of DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Further analysis identified that Peroxiredoxin 1, PRDX1, contributes to the DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage-induced nuclear reactive oxygen species. Moreover, PRDX1 loss lowers aspartate availability, which is required for the DNA damage-induced upregulation of de novo nucleotide synthesis. In the absence of PRDX1, cells accumulate replication stress and DNA damage, leading to proliferation defects that are exacerbated in the presence of etoposide, thus revealing a role for PRDX1 as a DNA damage surveillance factor.
    Keywords:  DNA damage response; Peroxiredoxin 1; aspartate metabolism; electron transport chain; reactive oxygen species scavenging