bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2023–12–03
five papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine
  1. Bidirectional interplay between metabolism and epigenetics in hematopoietic stem cells and leukemia.
  2. Acetyl-CoA is a key molecule for nephron progenitor cell pool maintenance.
  3. 2-Hydroxyglutarate modulates histone methylation at specific loci and alters gene expression via Rph1 inhibition.
  4. AHCY plays multiple roles in maintaining the identity and pluripotency of mouse embryonic stem cells.
  5. Comparison of colorimetric, fluorometric, and liquid chromatography-mass spectrometry assays for acetyl-coenzyme A.
  1. EMBO J. 2023 Nov 27. e112348
    Bidirectional interplay between metabolism and epigenetics in hematopoietic stem cells and leukemia.
    Yu Wei Zhang, Katharina Schönberger, Nina Cabezas-Wallscheid.
      During the last decades, remarkable progress has been made in further understanding the complex molecular regulatory networks that maintain hematopoietic stem cell (HSC) function. Cellular and organismal metabolisms have been shown to directly instruct epigenetic alterations, and thereby dictate stem cell fate, in the bone marrow. Epigenetic regulatory enzymes are dependent on the availability of metabolites to facilitate DNA- and histone-modifying reactions. The metabolic and epigenetic features of HSCs and their downstream progenitors can be significantly altered by environmental perturbations, dietary habits, and hematological diseases. Therefore, understanding metabolic and epigenetic mechanisms that regulate healthy HSCs can contribute to the discovery of novel metabolic therapeutic targets that specifically eliminate leukemia stem cells while sparing healthy HSCs. Here, we provide an in-depth review of the metabolic and epigenetic interplay regulating hematopoietic stem cell fate. We discuss the influence of metabolic stress stimuli, as well as alterations occurring during leukemic development. Additionally, we highlight recent therapeutic advancements toward eradicating acute myeloid leukemia cells by intervening in metabolic and epigenetic pathways.
    Keywords:  acute myeloid leukemia; epigenetics; hematopoietic stem cells; leukemia stem cells; metabolism
    DOI:  https://doi.org/10.15252/embj.2022112348
  2. Nat Commun. 2023 Nov 25. 14(1): 7733
    Acetyl-CoA is a key molecule for nephron progenitor cell pool maintenance.
    Fabiola Diniz, Nguyen Yen Nhi Ngo, Mariel Colon-Leyva, Francesca Edgington-Giordano, Sylvia Hilliard, Kevin Zwezdaryk, Jiao Liu, Samir S El-Dahr, Giovane G Tortelote.
      Nephron endowment at birth impacts long-term renal and cardiovascular health, and it is contingent on the nephron progenitor cell (NPC) pool. Glycolysis modulation is essential for determining NPC fate, but the underlying mechanism is unclear. Combining RNA sequencing and quantitative proteomics we identify 267 genes commonly targeted by Wnt activation or glycolysis inhibition in NPCs. Several of the impacted pathways converge at Acetyl-CoA, a co-product of glucose metabolism. Notably, glycolysis inhibition downregulates key genes of the Mevalonate/cholesterol pathway and stimulates NPC differentiation. Sodium acetate supplementation rescues glycolysis inhibition effects and favors NPC maintenance without hindering nephrogenesis. Six2Cre-mediated removal of ATP-citrate lyase (Acly), an enzyme that converts citrate to acetyl-CoA, leads to NPC pool depletion, glomeruli count reduction, and increases Wnt4 expression at birth. Sodium acetate supplementation counters the effects of Acly deletion on cap-mesenchyme. Our findings show a pivotal role of acetyl-CoA metabolism in kidney development and uncover new avenues for manipulating nephrogenesis and preventing adult kidney disease.
    DOI:  https://doi.org/10.1038/s41467-023-43513-7
  3. Life Sci Alliance. 2024 Feb;pii: e202302333. [Epub ahead of print]7(2):
    2-Hydroxyglutarate modulates histone methylation at specific loci and alters gene expression via Rph1 inhibition.
    Marios Gavriil, Marco Proietto, Nicole Paczia, Aurelien Ginolhac, Rashi Halder, Elena Valceschini, Thomas Sauter, Carole L Linster, Lasse Sinkkonen.
      2-Hydroxyglutarate (2-HG) is an oncometabolite that accumulates in certain cancers. Gain-of-function mutations in isocitrate dehydrogenase lead to 2-HG accumulation at the expense of alpha-ketoglutarate. Elevated 2-HG levels inhibit histone and DNA demethylases, causing chromatin structure and gene regulation changes with tumorigenic consequences. We investigated the effects of elevated 2-HG levels in Saccharomyces cerevisiae, a yeast devoid of DNA methylation and heterochromatin-associated histone methylation. Our results demonstrate genetic background-dependent gene expression changes and altered H3K4 and H3K36 methylation at specific loci. Analysis of histone demethylase deletion strains indicated that 2-HG inhibits Rph1 sufficiently to induce extensive gene expression changes. Rph1 is the yeast homolog of human KDM4 demethylases and, among the yeast histone demethylases, was the most sensitive to the inhibitory effect of 2-HG in vitro. Interestingly, Rph1 deficiency favors gene repression and leads to further down-regulation of already silenced genes marked by low H3K4 and H3K36 trimethylation, but abundant in H3K36 dimethylation. Our results provide novel insights into the genome-wide effects of 2-HG and highlight Rph1 as its preferential demethylase target.
    DOI:  https://doi.org/10.26508/lsa.202302333
  4. Biol Reprod. 2023 Nov 30. pii: ioad165. [Epub ahead of print]
    AHCY plays multiple roles in maintaining the identity and pluripotency of mouse embryonic stem cells.
    Qi Jiang, Shubing Lan, Fancheng Tan, Yiping Liang, Zhencheng Guo, Yanlin Hou, Hui Zhang, Guangming Wu, Zhonghua Liu.
      Adenosylhomocysteinase (AHCY), a key enzyme in the methionine cycle, is essential for the development of embryos and the maintenance of mESCs. However, the precise underlying mechanism of Ahcy in regulating pluripotency remains unclear. As the only enzyme that can hydrolyze S-adenosylhomocysteine in mammals, AHCY plays a critical role in the metabolic homeostasis, epigenetic remodeling, and transcriptional regulation. Here, we identified Ahcy as a direct target of OCT4 and unveiled that AHCY regulates the self-renewal and differentiation potency of mESCs through multiple mechanisms. Our study demonstrated that AHCY is required for the metabolic homeostasis of mESCs. We revealed the dual role of Ahcy in both transcriptional activation and inhibition, which is accomplished via the maintenance of H3K4me3 and H3K27me3, respectively. We found that Ahcy is required for H3K4me3-dependent transcriptional activation in mESCs. We also demonstrated that AHCY interacts with polycomb repressive complex 2 (PRC2), thereby maintaining the pluripotency of mESCs by sustaining the H3K27me3-regulated transcriptional repression of related genes. These results reveal a previously unrecognized OCT4-AHCY-PRC2 axis in the regulation of mESCs pluripotency and provide insights into the interplay between transcriptional factors, cellular metabolism, chromatin dynamics, and pluripotency regulation.
    Keywords:  AHCY; PRC2; epigenetics; mESCs; pluripotency
    DOI:  https://doi.org/10.1093/biolre/ioad165
  5. Anal Biochem. 2023 Nov 26. pii: S0003-2697(23)00370-6. [Epub ahead of print]685 115405
    Comparison of colorimetric, fluorometric, and liquid chromatography-mass spectrometry assays for acetyl-coenzyme A.
    Daniel S Kantner, Emily Megill, Anna Bostwick, Vicky Yang, Carmen Bekeova, Alexandria Van Scoyk, Erin L Seifert, Michael W Deininger, Nathaniel W Snyder.
      Acetyl-Coenzyme A is a central metabolite in catabolic and anabolic pathways as well as the acyl donor for acetylation reactions. Multiple quantitative measurement techniques for acetyl-CoA have been reported, including commercially available kits. Comparisons between techniques for acetyl-CoA measurement have not been reported. This lack of comparability between assays makes context-specific assay selection and interpretation of results reporting changes in acetyl-CoA metabolism difficult. We compared commercially available colorimetric ELISA and fluorometric enzymatic-based kits to liquid chromatography-mass spectrometry-based assays using tandem mass spectrometry (LC-MS/MS) and high-resolution mass spectrometry (LC-HRMS). The colorimetric ELISA kit did not produce interpretable results even with commercially available pure standards. The fluorometric enzymatic kit produced comparable results to the LC-MS-based assays depending on matrix and extraction. LC-MS/MS and LC-HRMS assays produced well-aligned results, especially when incorporating stable isotope-labeled internal standards. In addition, we demonstrated the multiplexing capability of the LC-HRMS assay by measuring a suite of short-chain acyl-CoAs in a variety of acute myeloid leukemia cell lines and patient cells.
    Keywords:  Acetyl-CoA; Mass spectrometry; Metabolite; Method comparison
    DOI:  https://doi.org/10.1016/j.ab.2023.115405
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