bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2023‒01‒29
three papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Plant J. 2023 Jan 27.
      Chromatin modifications shape the epigenome and are essential for gene expression reprogramming during plant development and adaptation to the changing environment. Chromatin modification enzymes require primary metabolic intermediates such as S-adenosyl-methionine, acetyl-CoA, alpha-glutarate, and NAD+ as substrates or cofactors. The availability of the metabolites depends on cellular nutrients, energy and reduction/oxidation (redox) states, and affects the activity of chromatin regulators and the epigenomic landscape. The changes in plant epigenome and the activity of epigenetic regulators in turn control cellular metabolism through transcriptional and post-translational regulation of metabolic enzymes. The interplay between metabolism and the epigenome constitutes a basis for metabolic control of plant growth and response to environmental changes. This review summarizes the recent advances regarding the metabolic control of plant chromatin regulators and epigenomes, which are involved in plant adaption to environmental stresses.
    Keywords:  Acetyl-CoA; Acetylation; Chromatin; Histone; Metabolism; Methylation; Redox; S-adenosyl methionine
  2. Sci Rep. 2023 Jan 27. 13(1): 1483
      Alkaliptosis is a recently discovered type of pH-dependent cell death used for tumor therapy. However, its underlying molecular mechanisms and regulatory networks are largely unknown. Here, we report that the acetate-activating enzyme acetyl-CoA short-chain synthase family member 2 (ACSS2) is a positive regulator of alkaliptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Using qPCR and western blot analysis, we found that the mRNA and protein expression of ACSS2 was upregulated in human PDAC cell lines (PANC1 and MiaPaCa2) in response to the classic alkaliptosis activator JTC801. Consequently, the knockdown of ACSS2 by shRNAs inhibited JTC801-induced cell death in PDAC cells, and was accompanied by an increase in cell clone formation and a decrease in intracellular pH. Mechanically, ACSS2-mediated acetyl-coenzyme A production and subsequent histone acetylation contributed to NF-κB-dependent CA9 downregulation, and this effect was enhanced by the histone deacetylase inhibitor trichostatin A. These findings may provide new insights for understanding the metabolic basis of alkaliptosis and establish a potential strategy for PDAC treatment.
  3. Nat Commun. 2023 Jan 25. 14(1): 405
      Stem cells undergo cellular division during their differentiation to produce daughter cells with a new cellular identity. However, the epigenetic events and molecular mechanisms occurring between consecutive cell divisions have been insufficiently studied due to technical limitations. Here, using the FUCCI reporter we developed a cell-cycle synchronised human pluripotent stem cell (hPSC) differentiation system for uncovering epigenome and transcriptome dynamics during the first two divisions leading to definitive endoderm. We observed that transcription of key differentiation markers occurs before cell division, while chromatin accessibility analyses revealed the early inhibition of alternative cell fates. We found that Activator protein-1 members controlled by p38/MAPK signalling are necessary for inducing endoderm while blocking cell fate shifting toward mesoderm, and that enhancers are rapidly established and decommissioned between different cell divisions. Our study has practical biomedical utility for producing hPSC-derived patient-specific cell types since p38/MAPK induction increased the differentiation efficiency of insulin-producing pancreatic beta-cells.