bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2024–11–17
six papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine
  1. A two-way relationship between histone acetylation and metabolism.
  2. Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation.
  3. Nuclear localization of MTHFD2 is required for correct mitosis progression.
  4. Metabolic rewiring controlled by HIF-1α tunes IgA-producing B-cell differentiation and intestinal inflammation.
  5. ATP citrate lyase is an essential player in the metabolic rewiring induced by PTEN loss during T-ALL development.
  6. Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity.
  1. Trends Biochem Sci. 2024 Nov 07. pii: S0968-0004(24)00230-5. [Epub ahead of print]
    A two-way relationship between histone acetylation and metabolism.
    Evelina Charidemou, Antonis Kirmizis.
      A link between epigenetics and metabolism was initially recognized because the cellular metabolic state is communicated to the genome through the concentration of intermediary metabolites that are cofactors of chromatin-modifying enzymes. Recently, an additional interaction was postulated due to the capacity of the epigenome to store substantial amounts of metabolites that could become available again to cellular metabolite pools. Here, we focus on histone acetylation and review recent evidence illustrating this reciprocal relationship: in one direction, signaling-induced acetyl-coenzyme A (acetyl-CoA) changes influence histone acetylation levels to regulate genomic functions, and in the opposite direction histone acetylation acts as an acetate reservoir to directly affect downstream acetyl-CoA-mediated metabolism. This review highlights the current understanding, experimental challenges, and future perspectives of this bidirectional interplay.
    Keywords:  acetate reservoir; aging; epigenetics; genome function; hyperacetylated histones; metabolic disease
    DOI:  https://doi.org/10.1016/j.tibs.2024.10.005
  2. J Clin Invest. 2024 Nov 15. pii: e176851. [Epub ahead of print]134(22):
    Lactate reprograms glioblastoma immunity through CBX3-regulated histone lactylation.
    Shuai Wang, Tengfei Huang, Qiulian Wu, Huairui Yuan, Xujia Wu, Fanen Yuan, Tingting Duan, Suchet Taori, Yingming Zhao, Nathaniel W Snyder, Dimitris G Placantonakis, Jeremy N Rich.
      Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades antitumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming toward glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia/macrophages induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of phagocytosis via transcriptional upregulation of CD47, a "don't eat me" signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) EP300 to induce increased EP300 substrate specificity toward lactyl-CoA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immuno-oncology therapies.
    Keywords:  Adult stem cells; Brain cancer; Epigenetics; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI176851
  3. Nat Commun. 2024 Nov 12. 15(1): 9529
    Nuclear localization of MTHFD2 is required for correct mitosis progression.
    Natalia Pardo-Lorente, Anestis Gkanogiannis, Luca Cozzuto, Antoni Gañez Zapater, Lorena Espinar, Ritobrata Ghose, Jacqueline Severino, Laura García-López, Rabia Gül Aydin, Laura Martin, Maria Victoria Neguembor, Evangelia Darai, Maria Pia Cosma, Laura Batlle-Morera, Julia Ponomarenko, Sara Sdelci.
      Subcellular compartmentalization of metabolic enzymes establishes a unique metabolic environment that elicits specific cellular functions. Indeed, the nuclear translocation of certain metabolic enzymes is required for epigenetic regulation and gene expression control. Here, we show that the nuclear localization of the mitochondrial enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) ensures mitosis progression. Nuclear MTHFD2 interacts with proteins involved in mitosis regulation and centromere stability, including the methyltransferases KMT5A and DNMT3B. Loss of MTHFD2 induces severe methylation defects and impedes correct mitosis completion. MTHFD2 deficient cells display chromosome congression and segregation defects and accumulate chromosomal aberrations. Blocking the catalytic nuclear function of MTHFD2 recapitulates the phenotype observed in MTHFD2 deficient cells, whereas restricting MTHFD2 to the nucleus is sufficient to ensure correct mitotic progression. Our discovery uncovers a nuclear role for MTHFD2, supporting the notion that translocation of metabolic enzymes to the nucleus is required to meet precise chromatin needs.
    DOI:  https://doi.org/10.1038/s41467-024-51847-z
  4. Cell Mol Immunol. 2024 Nov 14.
    Metabolic rewiring controlled by HIF-1α tunes IgA-producing B-cell differentiation and intestinal inflammation.
    Xianyi Meng, Sahar Asadi-Asadabad, Shan Cao, Rui Song, Zhen Lin, Mohammed Safhi, Yi Qin, Estelle Tcheumi Tactoum, Verena Taudte, Arif Ekici, Dirk Mielenz, Stefan Wirtz, Georg Schett, Aline Bozec.
      Germinal centers where B cells undergo clonal expansion and antibody affinity maturation are hypoxic microenvironments. However, the function of hypoxia-inducible factor (HIF)-1α in immunoglobulin production remains incompletely characterized. Here, we demonstrated that B cells lacking HIF-1α exhibited significantly lower glycolytic metabolism and impaired IgA production. Loss of HIF-1α in B cells affects IgA-producing B-cell differentiation and exacerbates dextran sodium sulfate (DSS)-induced colitis. Conversely, promoting HIF-1α stabilization via a PHD inhibitor roxadustat enhances IgA class switching and alleviates intestinal inflammation. Mechanistically, HIF-1α facilitates IgA class switching through acetyl-coenzyme A (acetyl-CoA) accumulation, which is essential for histone H3K27 acetylation at the Sα region. Consequently, supplementation with acetyl-CoA improved defective IgA production in Hif1a-deficient B cells and limited experimental colitis. Collectively, these findings highlight the critical importance of HIF-1α in IgA class switching and the potential for targeting the HIF-1α-dependent metabolic‒epigenetic axis to treat inflammatory bowel diseases and other inflammatory disorders.
    Keywords:  B cells; HIF-1α; Hypoxia; IgA; Intestinal inflammation
    DOI:  https://doi.org/10.1038/s41423-024-01233-y
  5. Blood Adv. 2024 Nov 15. pii: bloodadvances.2024013762. [Epub ahead of print]
    ATP citrate lyase is an essential player in the metabolic rewiring induced by PTEN loss during T-ALL development.
    Guillaume P Andrieu, Guillaume Hypolite, Mehdi Latiri, Estelle Balducci, Caroline Costa, Els Verhoeyen, Marianne Courgeon, Omran Allatif, Ivan Nemazanyy, Ganna Panasyuk, Kathryn E Wellen, Daniel Herranz, Laurent Genestier, Elizabeth A Macintyre, Vahid Asnafi, Melania Tesio.
      Alterations inactivating the tumor suppressor gene PTEN drive the development of solid and hematological cancers, such as T-cell acute lymphoblastic leukemia (T-ALL), whereby PTEN loss defines poor-prognosis patients. We investigated the metabolic rewiring induced by PTEN loss in T-ALL, aiming at identifying novel metabolic vulnerabilities. We showed that the enzyme ATP citrate lyase (ACLY) is strictly required for the transformation of thymic immature progenitors and for the growth of human T-ALL, which remain dependent on ACLY activity even upon transformation. Whereas PTEN mutant mice all died within 17 weeks, the concomitant ACLY deletion prevented disease initiation in 70% of the animals. In these animals, ACLY promoted BCL-2 epigenetic upregulation and prevented the apoptosis of pre-malignant DP thymocytes. Transcriptomic and metabolic analysis of primary T-ALL cells next translated our findings to the human pathology, showing that PTEN-altered T-ALL cells activate ACLY and are sensitive to its genetic targeting. ACLY activation thus represents a metabolic vulnerability with therapeutic potential for high-risk T-ALL patients.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013762
  6. Nat Commun. 2024 Nov 12. 15(1): 9515
    Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity.
    Lorena Espinar, Marta Garcia-Cao, Alisa Schmidt, Savvas Kourtis, Antoni Gañez Zapater, Carla Aranda-Vallejo, Ritobrata Ghose, Laura Garcia-Lopez, Ilir Sheraj, Natalia Pardo-Lorente, Marina Bantulà, Laura Pascual-Reguant, Evangelia Darai, Maria Guirola, Joan Montero, Sara Sdelci.
      Nuclear metabolism and DNA damage response are intertwined processes, but the precise molecular links remain elusive. Here, we explore this crosstalk using triple-negative breast cancer (TNBC) as a model, a subtype often prone to DNA damage accumulation. We show that the de novo purine synthesis enzyme IMPDH2 is enriched on chromatin in TNBC compared to other subtypes. IMPDH2 chromatin localization is DNA damage dependent, and IMPDH2 repression leads to DNA damage accumulation. On chromatin, IMPDH2 interacts with and modulates PARP1 activity by controlling the nuclear availability of NAD+ to fine-tune the DNA damage response. However, when IMPDH2 is restricted to the nucleus, it depletes nuclear NAD+, leading to PARP1 cleavage and cell death. Our study identifies a non-canonical nuclear role for IMPDH2, acting as a convergence point of nuclear metabolism and DNA damage response.
    DOI:  https://doi.org/10.1038/s41467-024-53877-z
This page is being maintained by Thomas Krichel. It was last updated on 2025‒12‒28 at 10:23.