bims-meprid 2023-03-05 papers

bims-meprid

Biomed News

on Metabolic-dependent epigenetic reprogramming in differentiation and disease

Issue of 2023‒03‒05
nine papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

(R)-2-hydroxyglutarate inhibits KDM5 histone lysine demethylases to drive transformation in IDH-mutant cancers.
Mechanism of action of lactic acid on histones in cancer.
Lactylation: Novel Epigenetic Regulatory and Therapeutic Opportunities.
Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions.
Chemoproteomic and Transcriptomic Analysis Reveals that O-GlcNAc Regulates Mouse Embryonic Stem Cell Fate through the Pluripotency Network.
O-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations.
Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies.
O-GlcNAc glycosylation orchestrates fate decision and niche function of bone marrow stromal progenitors.
Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism.

Cancer Discov. 2023 Feb 27. pii: CD-22-0825. [Epub ahead of print]

(R)-2-hydroxyglutarate inhibits KDM5 histone lysine demethylases to drive transformation in IDH-mutant cancers.

Kathryn Gunn, Matti Myllykoski, John Z Cao, Manna Ahmed, Bofu Huang, Betty Rouaisnel, Bill H Diplas, Michael M Levitt, Ryan Looper, John G Doench, Keith L Ligon, Harley I Kornblum, Samuel K McBrayer, Hai Yan, Cihangir Duy, Lucy A Godley, Peppi Koivunen, Julie-Aurore Losman.

Oncogenic mutations in isocitrate dehydrogenase (IDH)-1 and -2 occur in a wide range of cancers, including acute myeloid leukemia (AML) and glioma. Mutant IDH enzymes convert 2-oxoglutarate (2OG) to (R)-2-hydroxyglutarate ((R)-2HG)), an oncometabolite that is hypothesized to promote cellular transformation by dysregulating 2OG-dependent enzymes. The only (R)-2HG target that has been convincingly shown to contribute to transformation by mutant IDH is the myeloid tumor suppressor TET2. However, there is ample evidence to suggest that (R)-2HG has other functionally relevant targets in IDH-mutant cancers. Here, we show that (R)-2HG inhibits KDM5 histone lysine demethylases and that this inhibition contributes to cellular transformation in IDH-mutant AML and IDH-mutant glioma. These studies provide the first evidence of a functional link between dysregulation of histone lysine methylation and transformation in IDH-mutant cancers.

DOI: https://doi.org/10.1158/2159-8290.CD-22-0825
Antioxid Redox Signal. 2023 Feb 27.

Mechanism of action of lactic acid on histones in cancer.

Riccardo Sgarra, Sabrina Battista, Laura Cerchia, Guidalberto Manfioletti, Monica Fedele.

SIGNIFICANCE: Metabolic end products and intermediates can exert signaling functions as chemical sources for histone post-translational modifications, which remodel chromatin and affect gene expression. Among them, lactic acid is responsible for histone lactylation, a recently discovered histone mark that occurs in high lactate conditions, such as those resulting from the Warburg effect in cancer cells.RECENT ADVANCES: Late-breaking studies have advanced the knowledge on the mechanisms involved in histone lactylation, requiring independent non-enzyme-dependent and enzyme-dependent reactions, which is emerging as an important hallmark of cancer cells linking metabolic changes to gene expression reprogramming.
CRITICAL ISSUES: Here, we give an overview about this new epigenetic modification, focusing on its mechanism of action in tumors and tumor microenvironment.
FUTURE DIRECTIONS: Further investigation on the competition mechanism between lactylation and acetylation, as well as on the mechanisms by which lactate fluctuation can control a specific gene set in a given tissue are needed in the coming years to exploit new anti-cancer therapeutic approaches.

DOI: https://doi.org/10.1089/ars.2022.0190
Am J Physiol Endocrinol Metab. 2023 Mar 01.

Lactylation: Novel Epigenetic Regulatory and Therapeutic Opportunities.

Haoqin Fan, Fan Yang, Zhenghui Xiao, Haiyan Luo, Huaiyang Chen, Zhi Chen, Qiming Liu, Yunbin Xiao.

  Lactate, which is an end product of glycolysis, has traditionally been considered as a metabolic waste. However, numerous studies have demonstrated that lactate serves metabolic and nonmetabolic functions in physiological processes and multiple diseases. Cancer and pulmonary arterial hypertension have been shown to undergo metabolic reprogramming, which is accompanied by increased lactate production. Metabolic reprogramming and epigenetic modifications have been extensively linked; furthermore, posttranslational modifications of histones caused by metabolites play a vital role in epigenetic alterations. In this paper, we reviewed recent research on lactate-induced histone modifications and provided a new vision about the metabolic effect of glycolysis. Based on our review, the crosstalk between the metabolome and epigenome induced by glycolysis may indicate novel epigenetic regulatory and therapeutic opportunities. There is a magnificent progress of the interaction between metabolomics and epigenomics in recent decades, but many questions still remained to be investigated. Lactylation is found in different pathophysiological states and leads to diverse biological effects, however, only a few mechanisms of lactylation have been illustrated. Further research on lactylation would provide us with a better understanding of the crosstalk between the metabolomics and epigenomics.

Keywords:  Epigenetic regulatory; Glycolysis; Lactylation

DOI:  https://doi.org/10.1152/ajpendo.00159.2022
Cell Rep. 2023 Feb 26. pii: S2211-1247(23)00164-X. [Epub ahead of print]42(3): 112153

Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions.

Leticia Soriano-Baguet, Melanie Grusdat, Henry Kurniawan, Mohaned Benzarti, Carole Binsfeld, Anouk Ewen, Joseph Longworth, Lynn Bonetti, Luana Guerra, Davide G Franchina, Takumi Kobayashi, Veronika Horkova, Charlène Verschueren, Sergio Helgueta, Deborah Gérard, Tushar H More, Antonia Henne, Catherine Dostert, Sophie Farinelle, Antoine Lesur, Jean-Jacques Gérardy, Christian Jäger, Michel Mittelbronn, Lasse Sinkkonen, Karsten Hiller, Johannes Meiser, Dirk Brenner.

  Pyruvate dehydrogenase (PDH) is the central enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle. The importance of PDH function in T helper 17 (Th17) cells still remains to be studied. Here, we show that PDH is essential for the generation of a glucose-derived citrate pool needed for Th17 cell proliferation, survival, and effector function. In vivo, mice harboring a T cell-specific deletion of PDH are less susceptible to developing experimental autoimmune encephalomyelitis. Mechanistically, the absence of PDH in Th17 cells increases glutaminolysis, glycolysis, and lipid uptake in a mammalian target of rapamycin (mTOR)-dependent manner. However, cellular citrate remains critically low in mutant Th17 cells, which interferes with oxidative phosphorylation (OXPHOS), lipid synthesis, and histone acetylation, crucial for transcription of Th17 signature genes. Increasing cellular citrate in PDH-deficient Th17 cells restores their metabolism and function, identifying a metabolic feedback loop within the central carbon metabolism that may offer possibilities for therapeutically targeting Th17 cell-driven autoimmunity.

Keywords:  CP: Immunology; CP: Metabolism; IL-17; T cells; Th17 cells; acetyl-CoA; citrate; epigenetics; experimental autoimmune encephalomyelitis; glucose metabolism; histone acetylation; pyruvate dehydrogenase

DOI:  https://doi.org/10.1016/j.celrep.2023.112153
Angew Chem Int Ed Engl. 2023 Feb 27. e202300500

Chemoproteomic and Transcriptomic Analysis Reveals that O-GlcNAc Regulates Mouse Embryonic Stem Cell Fate through the Pluripotency Network.

Yi Hao, Xiang Li, Ke Qin, Yujie Shi, Yanwen He, Che Zhang, Bo Cheng, Xiwen Zhang, Guangyu Hu, Shuyu Liang, Qi Tang, Xing Chen.

  Self-renewal and differentiation of embryonic stem cells (ESCs) are influenced by protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification, but the underlying mechanism remains incompletely understood. Here, we report the identification of 979 O-GlcNAcylated proteins and 1,340 modification sites in mouse ESCs (mESCs) by using a chemoproteomics method. In addition to OCT4 and SOX2, the third core pluripotency transcription factor (PTF) NANOG was found to be modified and functionally regulated by O-GlcNAc. Upon differentiation along the neuronal lineage, the O-GlcNAc stoichiometry at 123 sites of 83 proteins-several of which were PTFs-was found to decline. Transcriptomic profiling reveals 2,456 differentially expressed genes responsive to OGT inhibition during differentiation, of which 901 are target genes of core PTFs. By acting on the core PTF network, suppression of O-GlcNAcylation upregulates neuron-related genes, thus contributing to the mESC fate determination.

Keywords:  Chemoproteomics; Embryonic stem cells; O-linked β-N-acetylglucosamine; Pluripotency transcription factors; Transcriptomics

DOI:  https://doi.org/10.1002/anie.202300500
bioRxiv. 2023 Feb 22. pii: 2023.02.22.529563. [Epub ahead of print]

O-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations.

Duc T Huynh, Jimin Hu, Jordan R Schneider, Kalina N Tsolova, Erik J Soderblom, Abigail J Watson, Jen-Tsan Chi, Chantell S Evans, Michael Boyce.

The neurofilament (NF) cytoskeleton is critical for neuronal morphology and function. In particular, the neurofilament-light (NF-L) subunit is required for NF assembly in vivo and is mutated in subtypes of Charcot-Marie-Tooth (CMT) disease. NFs are highly dynamic, and the regulation of NF assembly state is incompletely understood. Here, we demonstrate that human NF-L is modified in a nutrient-sensitive manner by O-linked-β- N -acetylglucosamine (O-GlcNAc), a ubiquitous form of intracellular glycosylation. We identify five NF-L O-GlcNAc sites and show that they regulate NF assembly state. Interestingly, NF-L engages in O-GlcNAc-mediated protein-protein interactions with itself and with the NF component α-internexin, implying that O-GlcNAc is a general regulator of NF architecture. We further show that NF-L O-GlcNAcylation is required for normal organelle trafficking in primary neurons, underlining its functional significance. Finally, several CMT-causative NF-L mutants exhibit perturbed O-GlcNAc levels and resist the effects of O-GlcNAcylation on NF assembly state, indicating a potential link between dysregulated O-GlcNAcylation and pathological NF aggregation. Our results demonstrate that site-specific glycosylation regulates NF-L assembly and function, and aberrant NF O-GlcNAcylation may contribute to CMT and other neurodegenerative disorders.

DOI: https://doi.org/10.1101/2023.02.22.529563
Aging (Albany NY). 2023 Feb 27. 15

Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies.

Ariel K Frame, J Wesley Robinson, Nader H Mahmoudzadeh, Jason M Tennessen, Anne F Simon, Robert C Cumming.

  The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory. Although studies in vertebrates have revealed that lactate shuttling is important for cognitive function, it is uncertain if this form of metabolic coupling is conserved in invertebrates or is influenced by age. Lactate dehydrogenase (Ldh) is a rate limiting enzyme that interconverts lactate and pyruvate. Here we genetically manipulated expression of Drosophila melanogaster lactate dehydrogenase (dLdh) in neurons or glia to assess the impact of altered lactate metabolism on invertebrate aging and long-term courtship memory at different ages. We also assessed survival, negative geotaxis, brain neutral lipids (the core component of lipid droplets) and brain metabolites. Both upregulation and downregulation of dLdh in neurons resulted in decreased survival and memory impairment with age. Glial downregulation of dLdh expression caused age-related memory impairment without altering survival, while upregulated glial dLdh expression lowered survival without disrupting memory. Both neuronal and glial dLdh upregulation increased neutral lipid accumulation. We provide evidence that altered lactate metabolism with age affects the tricarboxylic acid (TCA) cycle, 2-hydroxyglutarate (2HG), and neutral lipid accumulation. Collectively, our findings indicate that the direct alteration of lactate metabolism in either glia or neurons affects memory and survival but only in an age-dependent manner.

Keywords:  Drosophila melanogaster; astrocyte-neuron lactate shuttle (ANLS); courtship conditioning; dLdh; glia; lactate; lactate dehydrogenase; long-term memory

DOI:  https://doi.org/10.18632/aging.204565
Elife. 2023 Mar 02. pii: e85464. [Epub ahead of print]12

O-GlcNAc glycosylation orchestrates fate decision and niche function of bone marrow stromal progenitors.

Zengdi Zhang, Zan Huang, Mohamed Awad, Mohammed Elsalanty, James Cray, Lauren E Ball, Jason C Maynard, Alma L Burlingame, Hu Zeng, Kim C Mansky, Hai-Bin Ruan.

  In mammals, interactions between the bone marrow (BM) stroma and hematopoietic progenitors contribute to bone-BM homeostasis. Perinatal bone growth and ossification provide a microenvironment for the transition to definitive hematopoiesis; however, mechanisms and interactions orchestrating the development of skeletal and hematopoietic systems remain largely unknown. Here, we establish intracellular O-linked β-N-acetylglucosamine (O-GlcNAc) modification as a posttranslational switch that dictates the differentiation fate and niche function of early BM stromal cells (BMSCs). By modifying and activating RUNX2, O-GlcNAcylation promotes osteogenic differentiation of BMSCs and stromal IL-7 expression to support lymphopoiesis. In contrast, C/EBPβ-dependent marrow adipogenesis and expression of myelopoietic stem cell factor (SCF) is inhibited by O-GlcNAcylation. Ablating O-GlcNAc transferase (OGT) in BMSCs leads to impaired bone formation, increased marrow adiposity, as well as defective B-cell lymphopoiesis and myeloid overproduction in mice. Thus, the balance of osteogenic and adipogenic differentiation of BMSCs is determined by reciprocal O-GlcNAc regulation of transcription factors, which simultaneously shapes the hematopoietic niche.

Keywords:  biochemistry; chemical biology; developmental biology; mouse

DOI:  https://doi.org/10.7554/eLife.85464
Nat Commun. 2023 Mar 02. 14(1): 1187

Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism.

Pavan S Upadhyayula, Dominique M Higgins, Angeliki Mela, Matei Banu, Athanassios Dovas, Fereshteh Zandkarimi, Purvi Patel, Aayushi Mahajan, Nelson Humala, Trang T T Nguyen, Kunal R Chaudhary, Lillian Liao, Michael Argenziano, Tejaswi Sudhakar, Colin P Sperring, Benjamin L Shapiro, Eman R Ahmed, Connor Kinslow, Ling F Ye, Markus D Siegelin, Simon Cheng, Rajesh Soni, Jeffrey N Bruce, Brent R Stockwell, Peter Canoll.

Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification.

DOI: https://doi.org/10.1038/s41467-023-36630-w