bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2020‒11‒29
six papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Nat Commun. 2020 11 23. 11(1): 5927
      Mitochondrial acyl-coenzyme A species are emerging as important sources of protein modification and damage. Succinyl-CoA ligase (SCL) deficiency causes a mitochondrial encephalomyopathy of unknown pathomechanism. Here, we show that succinyl-CoA accumulates in cells derived from patients with recessive mutations in the tricarboxylic acid cycle (TCA) gene succinyl-CoA ligase subunit-β (SUCLA2), causing global protein hyper-succinylation. Using mass spectrometry, we quantify nearly 1,000 protein succinylation sites on 366 proteins from patient-derived fibroblasts and myotubes. Interestingly, hyper-succinylated proteins are distributed across cellular compartments, and many are known targets of the (NAD+)-dependent desuccinylase SIRT5. To test the contribution of hyper-succinylation to disease progression, we develop a zebrafish model of the SCL deficiency and find that SIRT5 gain-of-function reduces global protein succinylation and improves survival. Thus, increased succinyl-CoA levels contribute to the pathology of SCL deficiency through post-translational modifications.
  2. Clin Epigenetics. 2020 Nov 23. 12(1): 182
      Mitochondria are controlled by the coordination of two genomes: the mitochondrial and the nuclear DNA. As such, variations in nuclear gene expression as a consequence of mutations and epigenetic modifications can affect mitochondrial functionality. Conversely, the opposite could also be true. However, the relationship between mitochondrial dysfunction and epigenetics, such as nuclear DNA methylation, remains largely unexplored. Mitochondria function as central metabolic hubs controlling some of the main substrates involved in nuclear DNA methylation, via the one carbon metabolism, the tricarboxylic acid cycle and the methionine pathway. Here, we review key findings and highlight new areas of focus, with the ultimate goal of getting one step closer to understanding the genomic effects of mitochondrial dysfunction on nuclear epigenetic landscapes.
    Keywords:  DNA; DNA methylation; Haplogroups; Metabolism; Mitochondria; Nucleus
  3. Gene. 2020 Nov 19. pii: S0378-1119(20)30992-6. [Epub ahead of print] 145323
      Gene expression is the key to cellular functions and homeostasis. Histone modifications regulate chromatin dynamics and gene expression. Neuronal cell functions largely depend on fluxes of neurotransmitters for activation of chromatin and gene expression. New studies by Lepack et al. and Farrelly et al. recently demonstrated how tissue transglutaminase 2 (TGM2) mediated histone glutamine modifications, either dopaminylation in the dopaminergic reward pathway or serotonylation in the context of cellular differentiation and signaling regulate gene expression and decipher striking differences from their known functions. This opens new avenues of research in the field of epigenetics in general and neuroepigenetics as special; and to find out the enzymes responsible for the reversible reaction of histone de-dopaminylation and de-serotonylation.
    Keywords:  Epigenetics; Glutamine modifications; Neurotransmission; Tissue transglutaminase 2; Ventral tegmental area; dopaminylation of H3Q5; serotonylation of H3K4me3Q5
  4. Cell Mol Gastroenterol Hepatol. 2020 Nov 22. pii: S2352-345X(20)30190-9. [Epub ahead of print]
      BACKGROUND AND AIMS: Gut bacteria-derived short-chain fatty acids (SCFAs) play crucial roles in the maintenance of intestinal homeostasis. However, how SCFAs regulate epithelial turnover and tissue repair remain incompletely understood. In this study, we investigated how the SCFA propionate regulates cell migration to promote epithelial renewal and repair.METHODS: Mouse small intestinal epithelial cells (MSIE) and human Caco-2 cells were used to determine the effects of SCFAs on gene expression, proliferation, migration, and cell spreading in vitro. Video microscopy and single cell tracking were used to assess cell migration kinetically. 5-bromo-2'-deoxyuridine (BrdU) and hydroxyurea were used to assess the effects of SCFAs on migration in vivo. Lastly, an acute colitis model using dextran sulfate sodium (DSS) was used to examine the effects of SCFAs in vivo.
    RESULTS: Using video microscopy and single cell tracking, we found that propionate promoted intestinal epithelial cell migration by enhancing cell spreading and polarization, which led to increases in both cell speed and persistence. This novel function of propionate was dependent on inhibition of class I histone de-acetylases (HDAC) and GPR43 and required signal transducer and activator of transcription 3 (STAT3). Furthermore, using 5-bromo-2'-deoxyuridine (BrdU) and hydroxyurea in vivo, we found that propionate enhanced cell migration up the crypt-villus axis under homeostatic conditions, while also protecting against ulcer formation in experimental colitis.
    CONCLUSION: Our results demonstrate a mechanism by which propionate stimulates cell migration in an HDAC inhibition, GPR43, and STAT3 dependent manner, and suggest that propionate plays an important role in epithelial migration independent of proliferation.
    Keywords:  HDAC; IEC; Migration; Propionate; STAT3
  5. J Cancer Res Clin Oncol. 2020 Nov 21.
      BACKGROUND: To identify novel miRNAs implicated in prostate cancer metastasis.METHODS: Sixty-five prostate cancer tissues and paired pan-cancer tissues were sequenced. Novel miRNAs were re-analyzed by MIREAP program. Biological functions of miR-N5 were transwell experiment and colony formation. Target genes of miR-N5 were analyzed by bioinformatic analysis. Downstream of target gene was analyzed by The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC) databases and confirmed by CHIP experiment.
    RESULTS: We identified a novel miRNA-miR-N5, which was downregulated in PCa cells, PCa tissue, and in the serum of patients with PCa. Knockout of miR-N5 enhanced migration and invasiveness in vitro. miR-N5 specified targeted CREBBP 3'-UTR and inhibited CREBBP expression, which mediated H3K56 acetylation at the promoter of EGFR, β-catenin and CDH1.
    CONCLUSION: This study may shed the light on miR-N5 which influences metastasis via histone acetylation.
    Keywords:  CREBBP; Histone acetylation; Metastasis; MicroRNAs; Prostate cancer; miR-N5
  6. Mol Nutr Food Res. 2020 Nov 23. e2000734
      Nutrition during pregnancy plays a crucial role in pregnancy health and outcomes. One-carbon metabolism is involved in a variety of physiological processes in mammals, including nucleic acid synthesis, amino acid homeostasis (methionine, serine and glycine), epigenetic regulation, redox balance and neurodevelopment. Among the nutrients involved in one-carbon metabolism, only folate has been extensively studied for its effect on pregnancy. We reviewed the current evidence linking nutrients with one-carbon units during pregnancy to the development of oocytes, embryos and placentas as well as maternal and offspring health. We describe the sources of mammalian one-carbon units, the pathways active in mammalian one-carbon metabolism, the maternal and fetal needs for one-carbon units and their functions during pregnancy. The demand for one-carbon metabolism is highest during pregnancy, from the perspective of the entire lifetime of a mammal. The primary types of one-carbon metabolism in mammals are the folate cycle, methionine cycle and transsulfuration pathway, and the metabolites in one-carbon metabolism are linked to one another. The primary type of one-carbon metabolism varies at different pregnancy stages, which largely depends on the developmental characteristics and requirements for each stage of pregnancy (for example, the methylation programming of the embryo, neural development of the fetus, fetal growth and placenta development). Therefore, we call for an overall consideration of one-carbon metabolism requirements for different pregnancy stages, specifically, the balance of all the nutrients involved, not just one single nutrient in one-carbon metabolism. Moreover, we suggest the establishment of an ideal one-carbon metabolism requirement model according to the requirements for the different pregnancy stages to support optimal pregnancy outcomes and maternal and offspring health. This article is protected by copyright. All rights reserved.
    Keywords:  embryo development; epigenetic modification; neurodevelopment; one-carbon metabolism; pregnancy outcomes; redox homeostasis