bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2023–09–24
six papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine
  1. PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma.
  2. Reductive carboxylation epigenetically instructs T cell differentiation.
  3. BCL11B and the NuRD complex cooperatively guard T-cell fate and inhibit OPA1-mediated mitochondrial fusion in T cells.
  4. PARylated PDHE1α generates acetyl-CoA for local chromatin acetylation and DNA damage repair.
  5. Formate supplementation enhances anti-tumor CD8+ T cell fitness and efficacy of PD-1 blockade.
  6. Connections between metabolism and epigenetic modifications in cancer.
  1. Nat Cancer. 2023 Sep 18.
    PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma.
    Tim Wartewig, Jay Daniels, Miriam Schulz, Erik Hameister, Abhinav Joshi, Joonhee Park, Emma Morrish, Anuroop V Venkatasubramani, Filippo M Cernilogar, Frits H A van Heijster, Christian Hundshammer, Heike Schneider, Filippos Konstantinidis, Judith V Gabler, Christine Klement, Henry Kurniawan, Calvin Law, Yujin Lee, Sara Choi, Joan Guitart, Ignasi Forne, Jérôme Giustinani, Markus Müschen, Salvia Jain, David M Weinstock, Roland Rad, Nicolas Ortonne, Franz Schilling, Gunnar Schotta, Axel Imhof, Dirk Brenner, Jaehyuk Choi, Jürgen Ruland.
      The PDCD1-encoded immune checkpoint receptor PD-1 is a key tumor suppressor in T cells that is recurrently inactivated in T cell non-Hodgkin lymphomas (T-NHLs). The highest frequencies of PDCD1 deletions are detected in advanced disease, predicting inferior prognosis. However, the tumor-suppressive mechanisms of PD-1 signaling remain unknown. Here, using tractable mouse models for T-NHL and primary patient samples, we demonstrate that PD-1 signaling suppresses T cell malignancy by restricting glycolytic energy and acetyl coenzyme A (CoA) production. In addition, PD-1 inactivation enforces ATP citrate lyase (ACLY) activity, which generates extramitochondrial acetyl-CoA for histone acetylation to enable hyperactivity of activating protein 1 (AP-1) transcription factors. Conversely, pharmacological ACLY inhibition impedes aberrant AP-1 signaling in PD-1-deficient T-NHLs and is toxic to these cancers. Our data uncover genotype-specific vulnerabilities in PDCD1-mutated T-NHL and identify PD-1 as regulator of AP-1 activity.
    DOI:  https://doi.org/10.1038/s43018-023-00635-7
  2. Nature. 2023 Sep 20.
    Reductive carboxylation epigenetically instructs T cell differentiation.
    Alison Jaccard, Tania Wyss, Noelia Maldonado-Pérez, Jan A Rath, Alessio Bevilacqua, Jhan-Jie Peng, Anouk Lepez, Christine Von Gunten, Fabien Franco, Kung-Chi Kao, Nicolas Camviel, Francisco Martín, Bart Ghesquière, Denis Migliorini, Caroline Arber, Pedro Romero, Ping-Chih Ho, Mathias Wenes.
      Protective immunity against pathogens or cancer is mediated by the activation and clonal expansion of antigen-specific naive T cells into effector T cells. To sustain their rapid proliferation and effector functions, naive T cells switch their quiescent metabolism to an anabolic metabolism through increased levels of aerobic glycolysis, but also through mitochondrial metabolism and oxidative phosphorylation, generating energy and signalling molecules1-3. However, how that metabolic rewiring drives and defines the differentiation of T cells remains unclear. Here we show that proliferating effector CD8+ T cells reductively carboxylate glutamine through the mitochondrial enzyme isocitrate dehydrogenase 2 (IDH2). Notably, deletion of the gene encoding IDH2 does not impair the proliferation of T cells nor their effector function, but promotes the differentiation of memory CD8+ T cells. Accordingly, inhibiting IDH2 during ex vivo manufacturing of chimeric antigen receptor (CAR) T cells induces features of memory T cells and enhances antitumour activity in melanoma, leukaemia and multiple myeloma. Mechanistically, inhibition of IDH2 activates compensating metabolic pathways that cause a disequilibrium in metabolites regulating histone-modifying enzymes, and this maintains chromatin accessibility at genes that are required for the differentiation of memory T cells. These findings show that reductive carboxylation in CD8+ T cells is dispensable for their effector response and proliferation, but that it mainly produces a pattern of metabolites that epigenetically locks CD8+ T cells into a terminal effector differentiation program. Blocking this metabolic route allows the increased formation of memory T cells, which could be exploited to optimize the therapeutic efficacy of CAR T cells.
    DOI:  https://doi.org/10.1038/s41586-023-06546-y
  3. EMBO J. 2023 Sep 22. e113448
    BCL11B and the NuRD complex cooperatively guard T-cell fate and inhibit OPA1-mediated mitochondrial fusion in T cells.
    Rui Liao, Yi Wu, Le Qin, Zhiwu Jiang, Shixue Gou, Linfu Zhou, Qilan Hong, Yao Li, Jingxuan Shi, Yao Yao, Liangxue Lai, Yangqiu Li, Pentao Liu, Jean Paul Thiery, Dajiang Qin, Thomas Graf, Xingguo Liu, Peng Li.
      The nucleosome remodeling and histone deacetylase (NuRD) complex physically associates with BCL11B to regulate murine T-cell development. However, the function of NuRD complex in mature T cells remains unclear. Here, we characterize the fate and metabolism of human T cells in which key subunits of the NuRD complex or BCL11B are ablated. BCL11B and the NuRD complex bind to each other and repress natural killer (NK)-cell fate in T cells. In addition, T cells upregulate the NK cell-associated receptors and transcription factors, lyse NK-cell targets, and are reprogrammed into NK-like cells (ITNKs) upon deletion of MTA2, MBD2, CHD4, or BCL11B. ITNKs increase OPA1 expression and exhibit characteristically elongated mitochondria with augmented oxidative phosphorylation (OXPHOS) activity. OPA1-mediated elevated OXPHOS enhances cellular acetyl-CoA levels, thereby promoting the reprogramming efficiency and antitumor effects of ITNKs via regulating H3K27 acetylation at specific targets. In conclusion, our findings demonstrate that the NuRD complex and BCL11B cooperatively maintain T-cell fate directly by repressing NK cell-associated transcription and indirectly through a metabolic-epigenetic axis, providing strategies to improve the reprogramming efficiency and antitumor effects of ITNKs.
    Keywords:  CHD4; MBD2; MTA2; OPA1; T-cell fate
    DOI:  https://doi.org/10.15252/embj.2023113448
  4. Nat Struct Mol Biol. 2023 Sep 21.
    PARylated PDHE1α generates acetyl-CoA for local chromatin acetylation and DNA damage repair.
    Jun Zhang, Feng Chen, Yuan Tian, Wenchao Xu, Qian Zhu, Zhenhai Li, Lingyu Qiu, Xiaopeng Lu, Bin Peng, Xiangyu Liu, Haiyun Gan, Baohua Liu, Xingzhi Xu, Wei-Guo Zhu.
      Chromatin relaxation is a prerequisite for the DNA repair machinery to access double-strand breaks (DSBs). Local histones around the DSBs then undergo prompt changes in acetylation status, but how the large demands of acetyl-CoA are met is unclear. Here, we report that pyruvate dehydrogenase 1α (PDHE1α) catalyzes pyruvate metabolism to rapidly provide acetyl-CoA in response to DNA damage. We show that PDHE1α is quickly recruited to chromatin in a polyADP-ribosylation-dependent manner, which drives acetyl-CoA generation to support local chromatin acetylation around DSBs. This process increases the formation of relaxed chromatin to facilitate repair-factor loading, genome stability and cancer cell resistance to DNA-damaging treatments in vitro and in vivo. Indeed, we demonstrate that blocking polyADP-ribosylation-based PDHE1α chromatin recruitment attenuates chromatin relaxation and DSB repair efficiency, resulting in genome instability and restored radiosensitivity. These findings support a mechanism in which chromatin-associated PDHE1α locally generates acetyl-CoA to remodel the chromatin environment adjacent to DSBs and promote their repair.
    DOI:  https://doi.org/10.1038/s41594-023-01107-3
  5. Cancer Discov. 2023 Sep 20.
    Formate supplementation enhances anti-tumor CD8+ T cell fitness and efficacy of PD-1 blockade.
    Jared H Rowe, Ilaria Elia, Osmaan Shahid, Emily F Gaudiano, Natalia E Sifnugel, Sheila Johnson, Amy G Reynolds, Megan E Fung, Shakchhi Joshi, Martin W LaFleur, Joon Seok Park, Kristen E Pauken, Joshua D Rabinowitz, Gordon J Freeman, Marcia C Haigis, Arlene H Sharpe.
      The tumor microenvironment (TME) restricts anti-tumor CD8+ T cell function and immunotherapy responses. Cancer cells compromise metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate one carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T cell fitness and anti-tumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for the enhanced tumor control. Our data demonstrate formate provides metabolic support to CD8+ T cells reinvigorated by anti-PD-1 to overcome a metabolic vulnerability in 1C metabolism in the TME to further improve T cell function.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-1301
  6. Med Rev (Berl). 2021 Dec;1(2): 199-221
    Connections between metabolism and epigenetic modifications in cancer.
    Guangchao Wang, Jingdong J Han.
      How cells sense and respond to environmental changes is still a key question. It has been identified that cellular metabolism is an important modifier of various epigenetic modifications, such as DNA methylation, histone methylation and acetylation and RNA N6-methyladenosine (m6A) methylation. This closely links the environmental nutrient availability to the maintenance of chromatin structure and gene expression, and is crucial to regulate cellular homeostasis, cell growth and differentiation. Cancer metabolic reprogramming and epigenetic alterations are widely observed, and facilitate cancer development and progression. In cancer cells, oncogenic signaling-driven metabolic reprogramming modifies the epigenetic landscape via changes in the key metabolite levels. In this review, we briefly summarized the current evidence that the abundance of key metabolites, such as S-adenosyl methionine (SAM), acetyl-CoA, α-ketoglutarate (α-KG), 2-hydroxyglutarate (2-HG), uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) and lactate, affected by metabolic reprogramming plays an important role in dynamically regulating epigenetic modifications in cancer. An improved understanding of the roles of metabolic reprogramming in epigenetic regulation can contribute to uncover the underlying mechanisms of metabolic reprogramming in cancer development and identify the potential targets for cancer therapies.
    Keywords:  DNA methylation; RNA m6A; cancer metabolic reprogramming; epigenetic modifications; histone acetylation; histone methylation
    DOI:  https://doi.org/10.1515/mr-2021-0015
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