bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2020‒09‒06
eleven papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine


  1. Cell Discov. 2020 ;6 56
    Chen W, Zhang Z, Chang C, Yang Z, Wang P, Fu H, Wei X, Chen E, Tan S, Huang W, Sun L, Ni T, Yang Y, Wang Y.
      A bioenergetic balance between glycolysis and mitochondrial respiration is particularly important for stem cell fate specification. It however remains to be determined whether undifferentiated spermatogonia switch their preference for bioenergy production during differentiation. In this study, we found that ATP generation in spermatogonia was gradually increased upon retinoic acid (RA)-induced differentiation. To accommodate this elevated energy demand, RA signaling concomitantly switched ATP production in spermatogonia from glycolysis to mitochondrial respiration, accompanied by increased levels of reactive oxygen species. Disrupting mitochondrial respiration significantly blocked spermatogonial differentiation. Inhibition of glucose conversion to glucose-6-phosphate or pentose phosphate pathway also repressed the formation of c-Kit+ differentiating germ cells, suggesting that metabolites produced from glycolysis are required for spermatogonial differentiation. We further demonstrated that the expression levels of several metabolic regulators and enzymes were significantly altered upon RA-induced differentiation, with both RNA-seq and quantitative proteomic analyses. Taken together, our data unveil a critically regulated bioenergetic balance between glycolysis and mitochondrial respiration that is required for spermatogonial proliferation and differentiation.
    Keywords:  Cell biology; Stem cells
    DOI:  https://doi.org/10.1038/s41421-020-0183-x
  2. Int J Mol Sci. 2020 Aug 31. pii: E6331. [Epub ahead of print]21(17):
    Seo MK, Kim SG, Seog DH, Bahk WM, Kim SH, Park SW, Lee JG.
      Growing evidence suggests that early life stress (ELS) has long-lasting effects on glucocorticoid receptor (GR) expression and behavior via epigenetic changes of the GR exon 17 promoter. However, it remains unclear whether ELS regulates histone modifications of the GR exon 17 promoter across the life span. We investigated the effects of maternal separation (MS) on histone acetylation and methylation of GR exon 17 promoter in the hippocampus, according to the age of adults. Depression-like behavior and epigenetic regulation of GR expression were examined at young and middle adulthood in mice subjected to MS from postnatal day 1 to 21. In the forced swimming test, young adult MS mice showed no effect on immobility time, but middle-aged MS mice significantly increased immobility time. Young adult and middle-aged MS mice showed decreased GR expression. Their two ages showed decreased histone acetylation with increased histone deacetylases (HDAC5) levels, decreased permissive methylation, and increased repressive methylation at the GR exon 17 promoter. The extent of changes in gene expression and histone modification in middle adulthood was greater than in young adulthood. These results indicate that MS in early life causes long-term negative effects on behavior via histone modification of the GR gene across the life span.
    Keywords:  depression; early life stress; epigenetic; glucocorticoid receptor; hippocampus; histone modification
    DOI:  https://doi.org/10.3390/ijms21176331
  3. Nature. 2020 Sep 02.
    Bian Y, Li W, Kremer DM, Sajjakulnukit P, Li S, Crespo J, Nwosu ZC, Zhang L, Czerwonka A, Pawłowska A, Xia H, Li J, Liao P, Yu J, Vatan L, Szeliga W, Wei S, Grove S, Liu JR, McLean K, Cieslik M, Chinnaiyan AM, Zgodziński W, Wallner G, Wertel I, Okła K, Kryczek I, Lyssiotis CA, Zou W.
      Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours1-4, but the cause of this link is unknown. Here we show that tumour cells disrupt methionine metabolism in CD8+ T cells, thereby lowering intracellular levels of methionine and the methyl donor S-adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 and impaired T cell immunity. Mechanistically, tumour cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumour SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumour immunity. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumour-bearing mice and patients with colon cancer. Clinically, tumour SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Our results identify a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumour microenvironment. Thus, cancer methionine consumption is an immune evasion mechanism, and targeting cancer methionine signalling may provide an immunotherapeutic approach.
    DOI:  https://doi.org/10.1038/s41586-020-2682-1
  4. Int J Mol Sci. 2020 Sep 02. pii: E6356. [Epub ahead of print]21(17):
    He J, Zhang P, Shen L, Niu L, Tan Y, Chen L, Zhao Y, Bai L, Hao X, Li X, Zhang S, Zhu L.
      Short-chain fatty acids (SCFAs), particularly acetate, propionate and butyrate, are mainly produced by anaerobic fermentation of gut microbes. SCFAs play an important role in regulating energy metabolism and energy supply, as well as maintaining the homeostasis of the intestinal environment. In recent years, many studies have shown that SCFAs demonstrate physiologically beneficial effects, and the signalling pathways related to SCFA production, absorption, metabolism, and intestinal effects have been discovered. Two major signalling pathways concerning SCFAs, G-protein-coupled receptors (GPRCs) and histone deacetylases (HDACs), are well recognized. In this review, we summarize the recent advances concerning the biological properties of SCFAs and the signalling pathways in inflammation and glucose and lipid metabolism.
    Keywords:  glycose and lipid metabolism; inflammation; short-chain fatty acids; signalling pathways
    DOI:  https://doi.org/10.3390/ijms21176356
  5. Islets. 2020 Sep 02. 1-12
    Hoang M, Joseph JW.
      Anaplerosis and the associated mitochondrial metabolite transporters generate unique cytosolic metabolic signaling molecules that can regulate insulin release from pancreatic β-cells. It has been shown that mitochondrial metabolites, transported by the citrate carrier (CIC), dicarboxylate carrier (DIC), oxoglutarate carrier (OGC), and mitochondrial pyruvate carrier (MPC) play a vital role in the regulation of glucose-stimulated insulin secretion (GSIS). Metabolomic studies on static and biphasic insulin secretion, suggests that several anaplerotic derived metabolites, including α-ketoglutarate (αKG), are strongly associated with nutrient regulated insulin secretion. Support for a role of αKG in the regulation of insulin secretion comes from studies looking at αKG dependent enzymes, including hypoxia-inducible factor-prolyl hydroxylases (PHDs) in clonal β-cells, and rodent and human islets. This review will focus on the possible link between defective anaplerotic-derived αKG, PHDs, and the development of type 2 diabetes (T2D).
    Keywords:  Insulin; alpha-ketoglutarate; hypoxia-inducible factor-prolyl hydroxylases; islets
    DOI:  https://doi.org/10.1080/19382014.2020.1802183
  6. Stem Cell Reports. 2020 Aug 20. pii: S2213-6711(20)30333-7. [Epub ahead of print]
    Tsuchiya Y, Kitajima Y, Masumoto H, Ono Y.
      Muscle satellite cells are normally quiescent but are rapidly activated following muscle damage. Here, we investigated whether damaged myofibers influence the activation of satellite cells. Our findings revealed that satellite cells are directly activated by damaged-myofiber-derived factors (DMDFs). DMDFs induced satellite cells to enter the cell cycle; however, the cells stayed at the G1 phase and did not undergo S phase, and these cells were reversible to the quiescent-like state. Proteome analysis identified metabolic enzymes, including GAPDH, as DMDFs, whose recombinant proteins stimulated the activation of satellite cells. Satellite cells pre-exposed to the DMDFs demonstrated accelerated proliferation ex vivo. Treatment with recombinant GAPDH prior to muscle injury promoted expansion of the satellite cell population in vivo. Thus, our results indicate that DMDFs are not only a set of biomarkers for muscle damage, but also act as moonlighting proteins involved in satellite cell activation at the initial step of muscle regeneration.
    Keywords:  GAPDH; MYOD; PAX7; moonlighting; muscle damage; muscle regeneration; muscle stem cells; myokines; satellite cells; skeletal muscle
    DOI:  https://doi.org/10.1016/j.stemcr.2020.08.002
  7. Proteomics. 2020 Aug 31. e2000049
    Liu JF, Wu SF, Liu S, Sun X, Wang XM, Xu P, Chen HZ, Yang JT.
      Lysine crotonylation (Kcr) is a recently discovered post-translational modification that potentially regulates multiple biological processes. With an objective to expand the available crotonylation datasets, we performed LC-MS/MS using mouse liver samples under normal physiological conditions to obtain in vivo crotonylome. We used a label-free strategy and identified 10,034 Class I (localization probabilities > 0.75) crotonylated sites in 2,245 proteins. The KcrE, KcrD, and EKcr motifs were significantly enriched in the crotonylated peptides. The identified crotonylated proteins were mostly enzymes and primarily located in the cytoplasm and nucleus. Functional enrichment analysis based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that the crotonylated proteins were closely related to the purine-containing compound metabolic process, ribose phosphate metabolic process, carbon metabolism pathway, ribosome pathway, and a series of metabolism-associated biological processes. To the best of our knowledge, this research provides the first report on the mouse liver crotonylome. Furthermore, it offers additional evidence that crotonylation exists in non-histone proteins, and is likely involved in various biological processes. The mass spectrometry proteomics data have been deposited in the ProteomeXchange Consortium with the dataset identifiers PXD019145. This article is protected by copyright. All rights reserved.
    Keywords:  crotonylation; dataset; label-free; liver; mouse
    DOI:  https://doi.org/10.1002/pmic.202000049
  8. Trends Biochem Sci. 2020 Sep 01. pii: S0968-0004(20)30201-2. [Epub ahead of print]
    Separovich RJ, Pang CNI, Wilkins MR.
      Histone methylation is central to the regulation of eukaryotic transcription. Here, we review how the histone methylation system itself is regulated. There is substantial evidence that mammalian histone methyltransferases and demethylases are phosphorylated and regulated by upstream signalling pathways. Functional studies of specific phosphosites are revealing which kinases and pathways signal to the histone methylation system and are discovering the diverse effects of phosphorylation on enzyme function. Nevertheless, the majority of phosphosites have no known kinase or function and our understanding of how histone methylation is regulated is fragmentary. Improved approaches are needed to establish and study the key regulatory phosphorylation sites on histone methyltransferases and demethylases, to avoid focus on constitutive sites which may have little regulatory purpose.
    Keywords:  chromatin; demethylase; epigenetics; kinase; methyltransferase; signalling
    DOI:  https://doi.org/10.1016/j.tibs.2020.08.004
  9. Circulation. 2020 Sep 04.
    Madsen A, Höppner G, Krause J, Hirt MN, Laufer SD, Schweizer M, Tan WLW, Mosqueira D, Anene-Nzelu CG, Lim I, Foo RSY, Eschenhagen T, Stenzig J.
      Background: DNA methylation acts as a mechanism of gene transcription regulation. It has recently gained attention as a possible therapeutic target in cardiac hypertrophy and heart failure. However, its exact role in cardiomyocytes remains controversial. Thus, we knocked out the main de novo DNA methyltransferase in cardiomyocytes, DNMT3A, in human induced pluripotent stem cells (hiPSC). Functional consequences of DNA methylation-deficiency under control and stress conditions were then assessed in human engineered heart tissue (EHT) from knockout hiPSC-derived cardiomyocytes. Methods: DNMT3A was knocked out in hiPSCs by CRISPR/Cas9 gene editing. Fibrin-based EHTs were generated from knockout (KO) and control hiPSC-derived cardiomyocytes. Development and baseline contractility were analyzed by video-optical recording. EHTs were subjected to different stress protocols, including serum starvation, serum variation, and restrictive feeding. Molecular, histological and ultrastructural analyses were performed afterwards. Results: Knockout of DNMT3A in human cardiomyocytes had three main consequences for cardiomyocyte morphology and function: (1) Gene expression changes of contractile proteins such as higher atrial gene expression and lower MYH7/MYH6 ratio correlated with different contraction kinetics in knockout vs. wild-type. (2) Aberrant activation of the glucose/lipid metabolism regulator PPARγ was associated with accumulation of lipid vacuoles within KO cardiomyocytes. (3) HIF-1 protein instability was associated with impaired glucose metabolism and lower glycolytic enzyme expression, rendering KO EHTs sensitive to metabolic stress such as serum withdrawal and restrictive feeding. Conclusions: The results suggest an important role of DNA methylation in the normal homeostasis of cardiomyocytes and during cardiac stress, which could make it an interesting target for cardiac therapy.
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.119.044444
  10. Nat Metab. 2020 Aug 31.
    Carvalho-Santos Z, Cardoso-Figueiredo R, Elias AP, Tastekin I, Baltazar C, Ribeiro C.
      Cellular metabolic reprogramming is an important mechanism by which cells rewire their metabolism to promote proliferation and cell growth. This process has been mostly studied in the context of tumorigenesis, but less is known about its relevance for nonpathological processes and how it affects whole-animal physiology. Here, we show that metabolic reprogramming in Drosophila female germline cells affects nutrient preferences of animals. Egg production depends on the upregulation of the activity of the pentose phosphate pathway in the germline, which also specifically increases the animal's appetite for sugar, the key nutrient fuelling this metabolic pathway. We provide functional evidence that the germline alters sugar appetite by regulating the expression of the fat-body-secreted satiety factor Fit. Our findings demonstrate that the cellular metabolic program of a small set of cells is able to increase the animal's preference for specific nutrients through inter-organ communication to promote specific metabolic and cellular outcomes.
    DOI:  https://doi.org/10.1038/s42255-020-0266-x
  11. Cancer Discov. 2020 Sep;10(9): 1258-1260
    Janin M, Esteller M.
      In this issue, Deblois and colleagues show how taxane-resistant triple-negative breast cancer cells evade viral mimicry response as a result of metabolic alteration, DNA hypomethylation, and relocation of histone H3K27 trimethylation (H3K27me3). This adaptation confers a therapeutic vulnerability to the inhibition of the H3K27me3 methyltransferase EZH2 in resistant cells, leading to tumor growth inhibition by viral mimicry reactivation.See related article by Deblois et al., p. 1312.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-0947