bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2020‒11‒08
seven papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine


  1. Cell Rep. 2020 Nov 03. pii: S2211-1247(20)31322-X. [Epub ahead of print]33(5): 108333
    Haniuda K, Fukao S, Kitamura D.
      The germinal center (GC) reaction is essential for long-lived humoral immunity. However, molecular requirements for the induction of Bcl6, the master regulator for GC B cell differentiation, remain unclear. Through screening for cytokines and other stimuli that regulate Bcl6 expression, we identify IL-4 as the strongest inducer. IL-4 signaling alters the metabolomic profile in activated B cells and induces accumulation of the TCA cycle intermediate α-ketoglutarate (αKG), which is required for activation of the Bcl6 gene locus. Mechanistically, after IL-4 treatment, STAT6 bound to the known enhancers in the Bcl6 locus recruits UTX, a demethylase for the repressive histone mark H3K27me3 that requires αKG as a cofactor. In turn, the H3K27me3 demethylation activates the enhancers and transcription of the Bcl6 gene. We propose that IL-4-mediated metabolic reprogramming in B cells is pivotal for epigenomic activation of Bcl6 expression to promote GC B cell differentiation.
    Keywords:  B cell; Bcl6; H3K27me3; TCA cycle; differentiation; epigenomic remodeling; germinal center; histone demethylase; metabolism; α-ketoglutarate
    DOI:  https://doi.org/10.1016/j.celrep.2020.108333
  2. J Biol Chem. 2020 11 05. pii: jbc.REV120.014915. [Epub ahead of print]
    Sheikh MA, Starling Emerald B, Ansari SA.
      Embryonic and adult stem cells possess the capability of self-renewal and lineage specific differentiation. The intricate balance between self-renewal and differentiation is governed by developmental signals and cell type specific gene regulatory mechanisms. A perturbed intra/extracellular environment during lineage specification could affect stem cell fate decisions resulting in pathology. Growing evidence demonstrates that metabolic pathways govern epigenetic regulation of gene expression during stem cell fate commitment through the utilization of metabolic intermediates or end products of metabolic pathways as substrates for enzymatic histone/DNA modifications. UDP-GlcNAc is one such metabolite which acts as a substrate for enzymatic mono-glycosylation of various nuclear, cytosolic, and mitochondrial proteins on serine/threonine amino acid residues, a process termed protein O-GlcNAcylation. The levels of GlcNAc inside the cells depend on the nutrient availability, especially glucose. Thus, this metabolic sensor could modulate gene expression through O-GlcNAc modification of histones or other proteins in response to metabolic fluctuations. Herein, we review evidence demonstrating how stem cells couple metabolic inputs to gene regulatory pathways through O-GlcNAc-mediated epigenetic/transcriptional regulatory mechanisms to govern self-renewal and lineage specific differentiation programs. This review will serve as a primer for researchers seeking to better understand how O-GlcNAc influences stemness, and may catalyze the discovery of new stem cell-based therapeutic approaches.
    Keywords:  Cell fate determination; Epigenetics; Gene expression; O-GlcNAcylation; Transcription; cell metabolism; epigenetics; gene expression; gene transcription; stem cells
    DOI:  https://doi.org/10.1074/jbc.REV120.014915
  3. Cell Metab. 2020 Nov 03. pii: S1550-4131(20)30549-0. [Epub ahead of print]32(5): 699-701
    Xu K, Shyu A, Li MO.
      Nutrient acquisition and metabolism are integral components of cell growth, proliferation, and differentiation programs. In a recent study in Nature, Bian et al. (2020) revealed that cancer cells outcompete T cells for methionine uptake, resulting in diminished SAM production, attenuated H3K79 dimethylation, decreased STAT5 expression, and impaired T cell immunity to cancer.
    DOI:  https://doi.org/10.1016/j.cmet.2020.10.016
  4. Front Genet. 2020 ;11 997
    Li X, Chen X, Liu Y, Zhang P, Zheng Y, Zeng W.
      SETDB1, a histone H3 lysine 9 (H3K9) methyltransferase, is crucial in meiosis and embryo development. This study aimed to investigate whether SETDB1 was associated with spermatogonial stem cells (SSC) homeostasis. We found that knockdown of Setdb1 impaired cell proliferation, led to an increase in reactive oxygen species (ROS) level through NADPH oxidase, and Setdb1 deficiency activated ROS downstream signaling pathways, including JNK and p38 MAPK, which possibly contributed to SSC apoptosis. Melatonin scavenged ROS and rescued the phenotype of Setdb1 KD. In addition, we demonstrated that SETDB1 regulated NADPH oxidase 4 (Nox4) and E2F1. Therefore, this study uncovers the new roles of SETDB1 in mediating intracellular ROS homeostasis for the survival of SSC.
    Keywords:  H3K9me3; NOX4; ROS; SETDB1; spermatogonial stem cell
    DOI:  https://doi.org/10.3389/fgene.2020.00997
  5. JMA J. 2020 Jul 15. 3(3): 193-200
    Morita Y, Tohyama S.
      The heart, one of the more complex organs, is composed from a number of differentiated cells. In general, researchers consider that the cardiac cells are derived from the same origin as mesodermal cells, except neural crest cells. However, as the developmental stages proceed, cardiac mesodermal cells are differentiated into various types of cells via cardiac progenitors and demonstrate different programming in transcriptional network and epigenetic regulation in a spatiotemporal manner. In fact, the metabolic feature also changes dramatically during heart development and cardiac differentiation. Researchers reported that each type of cell exhibits different metabolic features that can be used to specifically identify them. Metabolism is a critical process for generating energy and biomass in all living cells and organisms and has been long regarded as a passenger, rather than an active driver, for intracellular status. However, recent studies revealed that metabolism influences self-renewal and cell fate specification via epigenetic changes directly or indirectly. Metabolism mirrors the physiological status of the cell and endogenous cellular activity; therefore, understanding the metabolic signature of each cell type serves as a guide for innovative methods of selecting and differentiating desired cell types. Stem cell biology and developmental biology hold great promise for cardiac regenerative therapy, for which, successful strategy depends on the precise translation of the philosophy of cardiac development in the early embryo to the cell production system. In this review, we focus on the metabolism during heart development and cardiac differentiation and discuss the next challenge to unlock the potential of cell biology for regenerative therapy based on metabolism.
    Keywords:  Cardiac differentiation; Heart Development; Metabolism; Pluripotent Stem Cells; Regenerative Medicine
    DOI:  https://doi.org/10.31662/jmaj.2020-0036
  6. Curr Opin Biotechnol. 2020 Oct 30. pii: S0958-1669(20)30144-0. [Epub ahead of print]68 72-88
    Ryan DG, Frezza C, O'Neill LA.
      A major question remaining in the field of evolutionary biology is how prokaryotic organisms made the leap to complex eukaryotic life. The prevailing theory depicts the origin of eukaryotic cell complexity as emerging from the symbiosis between an α-proteobacterium, the ancestor of present-day mitochondria, and an archaeal host (endosymbiont theory). A primary contribution of mitochondria to eukaryogenesis has been attributed to the mitochondrial genome, which enabled the successful internalisation of bioenergetic membranes and facilitated remarkable genome expansion. It has also been postulated that a key contribution of the archaeal host during eukaryogenesis was in providing 'archaeal histones' that would enable compaction and regulation of an expanded genome. Yet, how the communication between the host and the symbiont evolved is unclear. Here, we propose an evolutionary concept in which mitochondrial TCA cycle signalling was also a crucial player during eukaryogenesis enabling the dynamic control of an expanded genome via regulation of DNA and histone modifications. Furthermore, we discuss how TCA cycle remodelling is a common evolutionary strategy invoked by eukaryotic organisms to coordinate stress responses and gene expression programmes, with a particular focus on the TCA cycle-derived metabolite itaconate.
    DOI:  https://doi.org/10.1016/j.copbio.2020.09.014
  7. PLoS One. 2020 ;15(11): e0241122
    Bakalov V, Reyes-Uribe L, Deshpande R, Maloy AL, Shapiro SD, Angus DC, Chang CH, Le Moyec L, Wendell SG, Kaynar AM.
      Sepsis is the leading cause of death in hospitalized patients and beyond the hospital stay and these long-term sequelae are due in part to unresolved inflammation. Metabolic shift from oxidative phosphorylation to aerobic glycolysis links metabolism to inflammation and such a shift is commonly observed in sepsis under normoxic conditions. By shifting the metabolic state from aerobic glycolysis to oxidative phosphorylation, we hypothesized it would reverse unresolved inflammation and subsequently improve outcome. We propose a shift from aerobic glycolysis to oxidative phosphorylation as a sepsis therapy by targeting the pathways involved in the conversion of pyruvate into acetyl-CoA via pyruvate dehydrogenase (PDH). Chemical manipulation of PDH using dichloroacetic acid (DCA) will promote oxidative phosphorylation over glycolysis and decrease inflammation. We tested our hypothesis in a Drosophila melanogaster model of surviving sepsis infected with Staphylococcus aureus. Drosophila were divided into 3 groups: unmanipulated, sham and sepsis survivors, all treated with linezolid; each group was either treated or not with DCA for one week following sepsis. We followed lifespan, measured gene expression of Toll, defensin, cecropin A, and drosomycin, and levels of lactate, pyruvate, acetyl-CoA as well as TCA metabolites. In our model, metabolic effects of sepsis are modified by DCA with normalized lactate, TCA metabolites, and was associated with improved lifespan of sepsis survivors, yet had no lifespan effects on unmanipulated and sham flies. While Drosomycin and cecropin A expression increased in sepsis survivors, DCA treatment decreased both and selectively increased defensin.
    DOI:  https://doi.org/10.1371/journal.pone.0241122