bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2025–03–09
seven papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine
  1. ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation.
  2. Cytometry at the Intersection of Metabolism and Epigenetics in Lymphocyte Dynamics.
  3. ACLY Promotes Cardiac Fibrosis via the Regulation of DNL and Histone Acetylation.
  4. Histone Lysine Crotonylation Regulates Long-Term Memory Storage.
  5. Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects.
  6. Inhibition of ATP Citrate Lyase by Hydroxycitrate-Loaded Exosomes Suppresses the Survival of Lung Adenocarcinoma Cells.
  7. Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response.
  1. Nat Commun. 2025 Feb 28. 16(1): 2071
    ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation.
    Li Yang, Jianwei You, Xincheng Yang, Ruishu Jiao, Jie Xu, Yue Zhang, Wen Mi, Lingzhi Zhu, Youqiong Ye, Ruobing Ren, Delin Min, Meilin Tang, Li Chen, Fuming Li, Pingyu Liu.
      Senescence-associated secretory phenotype (SASP) mediates the biological effects of senescent cells on the tissue microenvironment and contributes to ageing-associated disease progression. ACSS2 produces acetyl-CoA from acetate and epigenetically controls gene expression through histone acetylation under various circumstances. However, whether and how ACSS2 regulates cellular senescence remains unclear. Here, we show that pharmacological inhibition and deletion of Acss2 in mice blunts SASP and abrogates the pro-tumorigenic and immune surveillance functions of senescent cells. Mechanistically, ACSS2 directly interacts with and promotes the acetylation of PAICS, a key enzyme for purine biosynthesis. The acetylation of PAICS promotes autophagy-mediated degradation of PAICS to limit purine metabolism and reduces dNTP pools for DNA repair, exacerbating cytoplasmic chromatin fragment accumulation and SASP. Altogether, our work links ACSS2-mediated local acetyl-CoA generation to purine metabolism through PAICS acetylation that dictates the functionality of SASP, and identifies ACSS2 as a potential senomorphic target to prevent senescence-associated diseases.
    DOI:  https://doi.org/10.1038/s41467-025-57334-3
  2. Cytometry A. 2025 Mar 07.
    Cytometry at the Intersection of Metabolism and Epigenetics in Lymphocyte Dynamics.
    Nicole Vaughn.
      Landmark studies at the turn of the century revealed metabolic reprogramming as a driving force for lymphocyte differentiation and function. In addition to metabolic changes, differentiating lymphocytes must remodel their epigenetic landscape to properly rewire their gene expression. Recent discoveries have shown that metabolic shifts can shape the fate of lymphocytes by altering their epigenetic state, bringing together these two areas of inquiry. The ongoing evolution of high-dimensional cytometry has enabled increasingly comprehensive analyses of metabolic and epigenetic landscapes in lymphocytes that transcend the technical limitations of the past. Here, we review recent insights into the interplay between metabolism and epigenetics in lymphocytes and how its dysregulation can lead to immunological dysfunction and disease. We also discuss the latest technical advances in cytometry that have enabled these discoveries and that we anticipate will advance future work in this area.
    DOI:  https://doi.org/10.1002/cyto.a.24919
  3. Hypertension. 2025 Mar 06.
    ACLY Promotes Cardiac Fibrosis via the Regulation of DNL and Histone Acetylation.
    Naoya Kuwahara, Manabu Nagao, Masakazu Shinohara, Kenta Kaneshiro, Takuo Emoto, Takeshi Yoshida, Terunobu Fukuda, Makoto Nishimori, Seimi Satomi-Kobayashi, Hiromasa Otake, Ken-Ichi Hirata, Tatsuro Ishida, Ryuji Toh.
       BACKGROUND: ATP citrate lyase (ACLY) is a key enzyme in de novo lipogenesis that generates acetyl-CoA from citrate. Although fatty acids are required for energy production and biomass synthesis in the heart, the regulatory mechanisms of ACLY-mediated de novo lipogenesis in pathological cardiac fibroblasts remain unknown. The aim of this study was to investigate the biological role of ACLY in cardiac remodeling.
    METHODS: Adeno-associated virus serotype 9-mediated shRNA targeting Acly was intravenously injected into C57BL/6J male mice. The mice were subsequently continuously infused with a mixture of angiotensin II and phenylephrine. Cardiac phenotypes were evaluated via histological staining. Cell proliferation assays, stable isotope tracing with 13C-labeled glucose, and chromatin immunoprecipitation assays were performed using human cardiac fibroblasts.
    RESULTS: ACLY expression was upregulated in the heart sections of mice treated with angiotensin II/phenylephrine, in particular in fibrotic areas. Masson trichrome staining revealed that Acly gene silencing significantly reduced cardiac fibrosis in these mice. Both siRNA-mediated ACLY knockdown and pharmacological ACLY inhibition suppressed the proliferation and expression of fibrous proteins in cultured human cardiac fibroblasts stimulated with transforming growth factor-β. Mechanistically, ACLY inhibition reduced de novo lipogenesis, limiting the fatty acid supply essential for cellular growth and proliferation. It also decreased H3K9 and H3K27 acetylation, in addition to the presence of acetylated H3K9 and H3K27 at the promoter regions of fibrotic genes.
    CONCLUSIONS: Our findings demonstrate that ACLY plays an important role in maladaptive cardiac fibrosis. ACLY could be a novel therapeutic target to prevent the development of heart failure.
    Keywords:  biomass; fibrosis; glucose; heart failure; serogroup
    DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.124.24088
  4. bioRxiv. 2025 Feb 19. pii: 2025.02.19.639114. [Epub ahead of print]
    Histone Lysine Crotonylation Regulates Long-Term Memory Storage.
    Utsav Mukherjee, Budhaditya Basu, Stacy E Beyer, Saaman Ghodsi, Nathan Robillard, Yann Vanrobaeys, Eric B Taylor, Ted Abel, Snehajyoti Chatterjee.
      Histone post-translational modifications (PTMs), particularly lysine acetylation (Kac), are critical epigenetic regulators of gene transcription underlying long-term memory consolidation. Beyond Kac, several other non-acetyl acylations have been identified, but their role in memory consolidation remains unknown. Here, we demonstrate histone lysine crotonylation (Kcr) as a key molecular switch of hippocampal memory storage. Spatial memory training induces distinct spatiotemporal patterns of Kcr induction in the dorsal hippocampus of mice. Through genetic and pharmacological manipulations, we show that reducing hippocampal Kcr levels impairs long-term memory, while increasing Kcr enhances memory. Utilizing single-nuclei multiomics, we delineate that Kcr enhancement during memory consolidation activates transcription of genes involved in neurotransmission and synaptic function within hippocampal excitatory neurons. Cell-cell communication analysis further inferred that Kcr enhancement strengthens glutamatergic signaling within principal hippocampal neurons. Our findings establish Kcr as a novel epigenetic mechanism governing memory consolidation and provide a foundation for therapeutic strategies targeting memory-related disorders.
    DOI:  https://doi.org/10.1101/2025.02.19.639114
  5. Elife. 2025 Mar 06. pii: RP97649. [Epub ahead of print]13
    Impaired yolk sac NAD metabolism disrupts murine embryogenesis with relevance to human birth defects.
    Kayleigh Bozon, Hartmut Cuny, Delicia Z Sheng, Ella M M A Martin, Alena Sipka, Paul Young, David T Humphreys, Sally L Dunwoodie.
      Congenital malformations can originate from numerous genetic or non-genetic factors but in most cases the causes are unknown. Genetic disruption of nicotinamide adenine dinucleotide (NAD) de novo synthesis causes multiple malformations, collectively termed Congenital NAD Deficiency Disorder (CNDD), highlighting the necessity of this pathway during embryogenesis. Previous work in mice shows that NAD deficiency perturbs embryonic development specifically when organs are forming. While the pathway is predominantly active in the liver postnatally, the site of activity prior to and during organogenesis is unknown. Here, we used a mouse model of human CNDD and assessed pathway functionality in embryonic livers and extraembryonic tissues via gene expression, enzyme activity and metabolic analyses. We found that the extra-embryonic visceral yolk sac endoderm exclusively synthesises NAD de novo during early organogenesis before the embryonic liver takes over this function. Under CNDD-inducing conditions, visceral yolk sacs had reduced NAD levels and altered NAD-related metabolic profiles, affecting embryo metabolism. Expression of requisite pathway genes is conserved in the equivalent yolk sac cell type in humans. Our findings show that visceral yolk sac-mediated NAD de novo synthesis activity is essential for mouse embryogenesis and its perturbation causes CNDD. As mouse and human yolk sacs are functionally homologous, our data improve the understanding of human congenital malformation causation.
    Keywords:  NAD; birth defects; congenital malformation; developmental biology; embryogenesis; metabolism; mouse; yolk sac
    DOI:  https://doi.org/10.7554/eLife.97649
  6. Appl Biochem Biotechnol. 2025 Mar 01.
    Inhibition of ATP Citrate Lyase by Hydroxycitrate-Loaded Exosomes Suppresses the Survival of Lung Adenocarcinoma Cells.
    Kanika Phutela, Priyanca Ahlawat, Jyotdeep Kaur, Amanjit Bal, Navneet Singh, Harkant Singh, Sadhna Sharma.
      The metabolic enzyme ATP citrate lyase is overexpressed in several cancers and links glucose metabolism with de novo fatty acid synthesis pathway by catalyzing the conversion of citrate into acetyl CoA and oxaloacetate. Potassium hydroxycitrate, its natural inhibitor, exhibits anticancer activity; however, its use is limited due to low bioavailability. This study aims to improve the efficacy of hydroxycitrate by its encapsulation in bovine milk exosome surface conjugated with folate for targeting lung cancer cells. The mean particle size of potassium hydroxycitrate-loaded exosomes (Exo-KH) and paclitaxel exosomes (Exo-Pac) was 183 nm and 174 nm; they had spherical morphology and encapsulation efficiency of 16.87 ± 2.78% and 27.65 ± 3.23%, respectively. In the in vitro study, Exo-KH suppressed the proliferation of A549 cells and significantly reduced ACLY mRNA expression. In addition to ACLY, EXO-KH also downregulated the mRNA expression of other crucial metabolic enzymes such as fatty acid synthase and isocitrate dehydrogenase 1. EXO-KH formulation caused significant increase in apoptosis rate (< 75%) and reactive oxygen species production and reduced ACLY protein expression in A549 cells. Moreover, the pharmacokinetic study revealed the sustained release of hydroxycitrate (half-life 22.74 h and clearance 0.13 µg/ml) from the exoformulation. Altogether, the study findings highlight the beneficial role of EXO-KH formulation against lung cancer.
    Keywords:  ATP citrate lyase; Adenocarcinoma; Exosomes; Folate; Potassium hydroxycitrate
    DOI:  https://doi.org/10.1007/s12010-025-05204-5
  7. Cell. 2025 Feb 27. pii: S0092-8674(25)00145-X. [Epub ahead of print]
    Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response.
    Xiadi He, Qiwei Wang, Xin Cheng, Weihua Wang, Yutong Li, Yabing Nan, Jiang Wu, Bingqiu Xiu, Tao Jiang, Johann S Bergholz, Hao Gu, Fuhui Chen, Guangjian Fan, Lianhui Sun, Shaozhen Xie, Junjie Zou, Sheng Lin, Yun Wei, James Lee, John M Asara, Ke Zhang, Lewis C Cantley, Jean J Zhao.
      Vitamin C (vitC) is essential for health and shows promise in treating diseases like cancer, yet its mechanisms remain elusive. Here, we report that vitC directly modifies lysine residues to form "vitcyl-lysine"-a process termed vitcylation. Vitcylation occurs in a dose-, pH-, and sequence-dependent manner in both cell-free systems and living cells. Mechanistically, vitC vitcylates signal transducer and activator of transcription-1 (STAT1)- lysine-298 (K298), impairing its interaction with T cell protein-tyrosine phosphatase (TCPTP) and preventing STAT1-Y701 dephosphorylation. This leads to enhanced STAT1-mediated interferon (IFN) signaling in tumor cells, increased major histocompatibility complex (MHC)/human leukocyte antigen (HLA) class I expression, and activation of anti-tumor immunity in vitro and in vivo. The discovery of vitcylation as a distinctive post-translational modification provides significant insights into vitC's cellular function and therapeutic potential, opening avenues for understanding its biological effects and applications in disease treatment.
    Keywords:  STAT1; immune response; protein modification; vitamin C; vitcylation
    DOI:  https://doi.org/10.1016/j.cell.2025.01.043
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