bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2021‒02‒21
nine papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine


  1. Neuron. 2021 Jan 21. pii: S0896-6273(21)00005-2. [Epub ahead of print]
    Li X, Zhang J, Li D, He C, He K, Xue T, Wan L, Zhang C, Liu Q.
      Astrocytes metabolically interact with neighboring neurons by providing multiple substances to neurons. How astrocytes regulate neural functions via altering the neuronal metabolic state remains elusive. Here, we demonstrate that astrocytic ApoE vectors a variety of microRNAs (miRNAs), and these miRNAs specifically silence genes involved in neuronal cholesterol biosynthesis, ultimately accounting for accumulation of the pathway-initiating substrate acetyl-CoA. Consequently, histone acetylation is promoted, and transcription is activated in neurons. Functionally, we demonstrate that ApoE-mediated neuronal histone acetylation leads to increased H3K27ac enrichment in the promoters of multiple neuronal immediate early genes and subsequently to enhanced memory consolidation in mice. Importantly, human ApoE4 vectors lower levels of miRNAs than ApoE3 and therefore is less capable of metabolic and epigenetic regulation in neurons. Collectively, our findings define an astrocytic ApoE-mediated neuronal epigenetic mechanism as a novel means through which astrocytes modulate brain connectivity and function.
    Keywords:  ApoE; acetyl-CoA; cholesterol metabolism; histone acetylation; memory consolidation; miRNA
    DOI:  https://doi.org/10.1016/j.neuron.2021.01.005
  2. Cell Rep. 2021 Feb 16. pii: S2211-1247(21)00057-7. [Epub ahead of print]34(7): 108744
    Wu D, Yan Y, Wei T, Ye Z, Xiao Y, Pan Y, Orme JJ, Wang D, Wang L, Ren S, Huang H.
      Acquisition of resistance to phosphatidylinositol 3-kinase (PI3K)/AKT-targeted monotherapy implies the existence of common resistance mechanisms independent of cancer type. Here, we demonstrate that PI3K/AKT inhibitors cause glycolytic crisis, acetyl-coenzyme A (CoA) shortage, and a global decrease in histone acetylation. In addition, PI3K/AKT inhibitors induce drug resistance by selectively augmenting histone H3 lysine 27 acetylation (H3K27ac) and binding of CBP/p300 and BRD4 proteins at a subset of growth factor and receptor (GF/R) gene loci. BRD4 occupation at these loci and drug-resistant cell growth are vulnerable to both bromodomain and histone deacetylase (HDAC) inhibitors. Little or no occupation of HDAC proteins at the GF/R gene loci underscores the paradox that cells respond equivalently to the two classes of inhibitors with opposite modes of action. Targeting this unique acetyl-histone-related vulnerability offers two clinically viable strategies to overcome PI3K/AKT inhibitor resistance in different cancers.
    DOI:  https://doi.org/10.1016/j.celrep.2021.108744
  3. J Exp Pathol (Wilmington). 2020 ;1(2): 60-70
    Cramer-Morales KL, Heer CD, Mapuskar KA, Domann FE.
      Previous studies showed that human cell line HEK293 lacking mitochondrial superoxide dismutase (MnSOD) exhibited decreased succinate dehydrogenase (SDH) activity, and mice lacking MnSOD displayed significant reductions in SDH and aconitase activities. Since MnSOD has significant effects on SDH activity, and succinate is a key regulator of TET enzymes needed for proper differentiation, we hypothesized that SOD2 loss would lead to succinate accumulation, inhibition of TET activity, and impaired erythroid precursor differentiation. To test this hypothesis, we genetically disrupted the SOD2 gene using the CRISPR/Cas9 genetic strategy in a human erythroleukemia cell line (HEL 92.1.7) capable of induced differentiation toward an erythroid phenotype. Cells obtained in this manner displayed significant inhibition of SDH activity and ~10-fold increases in cellular succinate levels compared to their parent cell controls. Furthermore, SOD2 -/- cells exhibited significantly reduced TET enzyme activity concomitant with decreases in genomic 5-hmC and corresponding increases in 5-mC. Finally, when stimulated with δ-aminolevulonic acid (δ-ALA), SOD2 -/- HEL cells failed to properly differentiate toward an erythroid phenotype, likely due to failure to complete the necessary global DNA demethylation program required for erythroid maturation. Together, our findings support the model of an SDH/succinate/TET axis and a role for succinate as a retrograde signaling molecule of mitochondrial origin that significantly perturbs nuclear epigenetic reprogramming and introduce MnSOD as a governor of the SDH/succinate/TET axis.
    Keywords:  DNA methylation; Epigenetic control; Gene expression; Iron homeostasis; Mitochondria; Retrograde signaling; Succinate dehydrogenase; Superoxide dismutase
  4. Front Oncol. 2020 ;10 620641
    Cuyàs E, Verdura S, Martin-Castillo B, Menendez JA.
      Metabolism can directly drive or indirectly enable an aberrant chromatin state of cancer cells. The physiological and molecular principles of the metabolic link to epigenetics provide a basis for pharmacological modulation with the anti-diabetic biguanide metformin. Here, we briefly review how metabolite-derived chromatin modifications and the metabolo-epigenetic machinery itself are both amenable to modification by metformin in a local and a systemic manner. First, we consider the capacity of metformin to target global metabolic pathways or specific metabolic enzymes producing chromatin-modifying metabolites. Second, we examine its ability to directly or indirectly fine-tune the activation status of chromatin-modifying enzymes. Third, we envision how the interaction between metformin, diet and gut microbiota might systemically regulate the metabolic inputs to chromatin. Experimental and clinical validation of metformin's capacity to change the functional outcomes of the metabolo-epigenetic link could offer a proof-of-concept to therapeutically test the metabolic adjustability of the epigenomic landscape of cancer.
    Keywords:  cancer; chromatin; diet; epigenetics; metabolism; metformin; microbiota
    DOI:  https://doi.org/10.3389/fonc.2020.620641
  5. Cancer Discov. 2021 Jan 27. pii: candisc.1227.2020. [Epub ahead of print]
    Egan G, Khan DH, Lee JB, Mirali S, Zhang L, Schimmer AD.
      Mitochondria are involved in many biological processes including cellular homeostasis, energy generation and apoptosis. Moreover, mitochondrial and metabolic pathways are interconnected with gene expression to regulate cellular functions such as cell growth, survival, differentiation and immune recognition. Metabolites and mitochondrial enzymes regulate chromatin modifying-enzymes, chromatin remodeling, and transcription regulators. Deregulation of mitochondrial pathways and metabolism leads to alterations in gene expression that promotes cancer development, progression and evasion of the immune system. This review highlights how mitochondrial and metabolic pathways function as a central mediator to control gene expression, specifically on stem cell functions, differentiation and immune response in leukemia.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1227
  6. Front Cell Dev Biol. 2021 ;9 609984
    Nakamura N, Shi X, Darabi R, Li Y.
      Cellular reprogramming is a fundamental topic in the research of stem cells and molecular biology. It is widely investigated and its understanding is crucial for learning about different aspects of development such as cell proliferation, determination of cell fate and stem cell renewal. Other factors involved during development include hypoxia and epigenetics, which play major roles in the development of tissues and organs. This review will discuss the involvement of hypoxia and epigenetics in the regulation of cellular reprogramming and how interplay between each factor can contribute to different cellular functions as well as tissue regeneration.
    Keywords:  cellular reprogramming; epigenetic; hypoxia; muscle; stem cells
    DOI:  https://doi.org/10.3389/fcell.2021.609984
  7. Exp Dermatol. 2021 Feb 18.
    Wagner RN, Piñón Hofbauer J, Wally V, Kofler B, Schmuth M, De Rosa L, De Luca M, Bauer JW.
      Continuous exposure of the skin to environmental, mechanical, and chemical stress necessitates constant self-renewal of the epidermis to maintain its barrier function. This self-renewal ability is attributed to epidermal stem cells (EPSCs), which are long-lived, multipotent cells located in the basal layer of the epidermis. Epidermal homeostasis - coordinated proliferation and differentiation of EPSCs - relies on fine-tuned adaptations in gene expression which in turn are tightly associated with specific epigenetic signatures and metabolic requirements. In this review, we will briefly summarize basic concepts of EPSC biology and epigenetic regulation with relevance to epidermal homeostasis. We will highlight the intricate interplay between mitochondrial energy metabolism and epigenetic events - including miRNA-mediated mechanisms - and discuss how the loss of epigenetic regulation and epidermal homeostasis manifests in skin disease. Discussion of inherited epidermolysis bullosa (EB) and disorders of cornification will focus on evidence for epigenetic deregulation and failure in epidermal homeostasis, including stem cell exhaustion and signs of premature aging. We reason that the epigenetic and metabolic component of epidermal homeostasis is significant and warrants close attention. Charting epigenetic and metabolic complexities also represents an important step in the development of future systemic interventions aimed at restoring epidermal homeostasis and ameliorating disease burden in severe skin conditions.
    Keywords:  Epidermolysis bullosa (EB); epidermal stem cells (EPSCs); epigenetics; keratinocytes; miRNAs; mitochondria
    DOI:  https://doi.org/10.1111/exd.14305
  8. Front Genet. 2020 ;11 616083
    Wei X, Cai M, Jin L.
      Parkinson's means Parkinson's disease, a chronic degenerative disease of central nervous system. The main area which is affected by this disease is motor system. Since it firstly founded by James Parkinson in his 1817 publication, nowadays, people still have lots of questions about this disease. This review mainly summarizes the epigenetics of Parkinson's. DNA methylation is one of the epigenetic mechanisms of Parkinson's. During the development of disease, global hypomethylation, and hypermethylation happen in different areas of patients. Another epigenetic mechanism is histone modification. People believe that some metals can induce Parkinson's disease by modulating epigenetic mechanisms. This review summarizes the relationships between different metals and Parkinson's disease. However, the specific roles of most metals in epigenetics are still unknown, which need further research.
    Keywords:  DNA methylation; Parkinson’s disease; epigenetic; metal; synucleinopathy
    DOI:  https://doi.org/10.3389/fgene.2020.616083
  9. Front Nutr. 2020 ;7 612115
    Kohil A, Al-Asmakh M, Al-Shafai M, Terranegra A.
      The autoimmune disease, Type 1 Diabetes Mellitus (T1DM), results in the destruction of pancreatic β-cells, and the International Diabetes Federation reports that its incidence is increasing worldwide. T1DM is a complex disease due to the interaction between genetic and environmental factors. Certain dietary patterns and nutrients are known to cause epigenetic modifications in physiological conditions and diseases. However, the interplay between diet and epigenetics is not yet well-understood in the context of T1DM. Several studies have described epigenetic mechanisms involved in the autoimmune reactions that destroy the β-cells, but few explored diet components as potential triggers for epigenetic modifications. Clarifying the link between diet and epigenome can provide new insights into the pathogenesis of T1DM, potentially leading to new diagnostic and therapeutic approaches. In this mini review, we shed light on the influence of the diet-epigenome axis on the pathophysiology of T1DM.
    Keywords:  DNA methylation; diet; epigenetics; histone modifications; micro-RNA; type 1 diabetes
    DOI:  https://doi.org/10.3389/fnut.2020.612115