bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2021‒01‒17
eleven papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine


  1. J Biol Chem. 2020 Dec 01. pii: S0021-9258(20)00021-6. [Epub ahead of print]296 100035
    Sheikh MA, Emerald BS, 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 that 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:  O-GlcNAcylation; cell fate determination; epigenetics; gene expression; transcription
    DOI:  https://doi.org/10.1074/jbc.REV120.014915
  2. Free Radic Biol Med. 2021 Jan 08. pii: S0891-5849(20)31688-9. [Epub ahead of print]
    Davison GW, Irwin RE, Walsh CP.
      The prevalence of type 2 diabetes mellitus (T2DM) continues to rise globally. Yet the aetiology and pathophysiology of this noncommunicable, polygenic disease, is poorly understood. Lifestyle factors, such as poor dietary intake, lack of exercise, and abnormal glycaemia, are purported to play a role in disease onset and progression, and these environmental factors may disrupt specific epigenetic mechanisms, leading to a reprogramming of gene transcription. The hyperglycaemic cell per se, alters epigenetics through chemical modifications to DNA and histones via metabolic intermediates such as succinate, α-ketoglutarate and O-GlcNAc. To illustrate, α-ketoglutarate is considered a salient co-factor in the activation of the ten-eleven translocation (TET) dioxygenases, which drives DNA demethylation. On the contrary, succinate and other mitochondrial tricarboxylic acid cycle intermediates, inhibit TET activity predisposing to a state of hypermethylation. Hyperglycaemia depletes intracellular ascorbic acid, and damages DNA by enhancing the production of reactive oxygen species (ROS); this compromised cell milieu exacerbates the oxidation of 5-methylcytosine alongside a destabilisation of TET. These metabolic connections may regulate DNA methylation, affecting gene transcription and pancreatic islet β-cell function in T2DM. This complex interrelationship between metabolism and epigenetic alterations may provide a conceptual foundation for understanding how pathologic stimuli modify and control the intricacies of T2DM. As such, this narrative review will comprehensively evaluate and detail the interplay between metabolism and epigenetic modifications in T2DM.
    Keywords:  DNA Methylation; Histone Modifications; Metabolism; Type 2 Diabetes Mellitus
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2020.12.025
  3. Free Radic Biol Med. 2021 Jan 12. pii: S0891-5849(21)00014-9. [Epub ahead of print]
    Hitchler MJ, Domann FE.
      The development of multicellular organisms involves the unpacking of a complex genetic program. Extensive characterization of discrete developmental steps has revealed the genetic program is controlled by an epigenetic state. Shifting the epigenome is a group of epigenetic enzymes that modify DNA and proteins to regulate cell type specific gene expression. While the role of these modifications in development has been established, the input(s) responsible for electing changes in the epigenetic state remains unknown. Development is also associated dynamic changes in cellular metabolism, redox, free radical production, and oxygen availability. It has previously been postulated that these changes are causal in development by affecting gene expression. This suggests that oxygen is a morphogenic compound that impacts the removal of epigenetic marks. Likewise, metabolism and reactive oxygen species influence redox signaling through iron and glutathione to limit the availability of key epigenetic cofactors such as α-ketoglutarate, ascorbate, NAD+ and S-adenosylmethionine. Given the close relationship between these cofactors and epigenetic marks it seems likely that the two are linked. Here we describe how changing these inputs might affect the epigenetic state during development to drive gene expression. Combined, these cofactors and reactive oxygen species constitute the epigenetic landscape guiding cells along differing developmental paths.
    Keywords:  DNA methylation; Demethylation; Epigenetics; HIF; Jumanji; S-adenosylmethionine; TET; development; glutathione; histone
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.01.008
  4. Biochim Biophys Acta Mol Cell Res. 2021 Jan 12. pii: S0167-4889(21)00019-7. [Epub ahead of print] 118965
    Yu Y, Moretti IF, Grzeschik NA, Sibon OCM, Schepers H.
      Coenzyme A (CoA) is a key molecule in cellular metabolism including the tricarboxylic acid cycle, fatty acid synthesis, amino acid synthesis and lipid metabolism. Moreover, CoA is required for biological processes like protein post-translational modifications (PTMs) including acylation. CoA levels affect the amount of histone acetylation and thereby modulate gene expression. A direct influence of CoA levels on other PTMs, like CoAlation and 4'-phosphopantetheinylation has been relatively less addressed and will be discussed here. Increased CoA levels are associated with increased CoAlation, whereas decreased 4'-phosphopantetheinylation is observed under circumstances of decreased CoA levels. We discuss how these two PTMs can positively or negatively influence target proteins depending on CoA levels. This review highlights the impact of CoA levels on post-translational modifications, their counteractive interplay and the far-reaching consequences thereof.
    DOI:  https://doi.org/10.1016/j.bbamcr.2021.118965
  5. FASEB J. 2021 Feb;35(2): e21316
    Ye Q, Zeng X, Wang S, Zeng X, Yang G, Ye C, Cai S, Chen M, Li S, Qiao S.
      Maintaining ovarian steroidogenesis is of critical importance, considering that steroid hormones are required for successful establishment and maintenance of pregnancy and proper development of embryos and fetuses. Investigating the mechanism that butyrate modulates the ovarian steroidogenesis is beneficial for understanding the impact of lipid nutrition on steroidogenesis. Herein, we identified that butyrate improved estradiol and progesterone synthesis in rat primary ovarian granulosa cells and human granulosa KGN cells and discovered the related mechanism. Our data indicated that butyrate was sensed by GPR41 and GPR43 in ovarian granulosa cells. Butyrate primarily upregulated the acetylation of histone H3K9 (H3K9ac). Chromatin immune-precipitation and sequencing (ChIP-seq) data of H3K9ac revealed the influenced pathways involving in the mitochondrial function (including cellular metabolism and steroidogenesis) and cellular antioxidant capacity. Additionally, increasing H3K9ac by butyrate further stimulated the PPARγ/CD36/StAR pathways to increase ovarian steroidogenesis and activated PGC1α to enhance mitochondrial dynamics and alleviate oxidative damage. The improvement in antioxidant capacity and mitochondrial dynamics by butyrate enhanced ovarian steroidogenesis. Collectively, butyrate triggers histone H3K9ac to activate steroidogenesis through PPARγ and PGC1α pathways in ovarian granulosa cells.
    Keywords:  estradiol; mitochondrial dynamics; mitochondrial function; oxidative stress; progesterone
    DOI:  https://doi.org/10.1096/fj.202000444R
  6. Semin Cancer Biol. 2021 Jan 09. pii: S1044-579X(20)30281-9. [Epub ahead of print]
    Sundaram MK, R P, Haque S, Akhter N, Khan S, Ahmed S, Hussain A.
      Cell cycle, growth, survival and metabolism are tightly regulated together and failure in cellular regulation leads to carcinogenesis. Several signaling pathways like the PI3K, WNT, MAPK and NFKb pathway exhibit aberrations in cancer and help achieve hallmark capabilities. Clinical research and in vitro studies have highlighted the role of epigenetic alterations in cancer onset and development. Altered gene expression patterns enabled by changes in DNA methylation, histone modifications and RNA processing have proven roles in cancer hallmark acquisition. The reversible nature of epigenetic processes offers robust therapeutic targets. Dietary bioactive compounds offer a vast compendium of effective therapeutic moieties. Isothiocyanates (ITCs) sourced from cruciferous vegetables demonstrate anti-proliferative, pro-apoptotic, anti-inflammatory, anti-migratory and anti-angiogenic effect against several cancers. ITCs also modulate the redox environment, modulate signaling pathways including PI3K, MAPK, WNT, and NFkB. They also modulate the epigenetic machinery by regulating the expression and activity of DNA methyltransferases, histone modifiers and miRNA. This further enhances their transcriptional modulation of key cellular regulators. In this review, we comprehensively assess the impact of ITCs such as sulforaphane, phenethyl isothiocyanate, benzyl isothiocyanate and allyl isothiocyanate on cancer and document their effect on various molecular targets. Overall, this will facilitate consolidation of the current understanding of the anti-cancer and epigenetic modulatory potential of these compounds and recognize the gaps in literature. Further, we discuss avenues of future research to develop these compounds as potential therapeutic entities.
    Keywords:  AITC; BITC; PEITC; epigenetics; isothiocyanate; sulforaphane
    DOI:  https://doi.org/10.1016/j.semcancer.2020.12.021
  7. Nutrients. 2021 Jan 08. pii: E179. [Epub ahead of print]13(1):
    Erber LN, Luo A, Gong Y, Beeson M, Tu M, Tran P, Chen Y.
      Micronutrient sensing is critical for cellular growth and differentiation. Deficiencies in essential nutrients such as iron strongly affect neuronal cell development and may lead to defects in neuronal function that cannot be remedied by subsequent iron supplementation. To understand the adaptive intracellular responses to iron deficiency in neuronal cells, we developed and utilized a Stable Isotopic Labeling of Amino acids in Cell culture (SILAC)-based quantitative phosphoproteomics workflow. Our integrated approach was designed to comprehensively elucidate the changes in phosphorylation signaling under both acute and chronic iron-deficient cell models. In addition, we analyzed the differential cellular responses between iron deficiency and hypoxia (oxygen-deprived) in neuronal cells. Our analysis identified nearly 16,000 phosphorylation sites in HT-22 cells, a hippocampal-derived neuronal cell line, more than ten percent of which showed at least 2-fold changes in response to either hypoxia or acute/chronic iron deficiency. Bioinformatic analysis revealed that iron deficiency altered key metabolic and epigenetic pathways including the phosphorylation of proteins involved in iron sequestration, glutamate metabolism, and histone methylation. In particular, iron deficiency increased glutamine-fructose-6-phosphate transaminase (GFPT1) phosphorylation, which is a key enzyme in the glucosamine biosynthesis pathway and a target of 5' AMP-activated protein kinase (AMPK), leading to reduced GFPT1 enzymatic activity and consequently lower global O-GlcNAc modification in neuronal cells. Taken together, our analysis of the phosphoproteome dynamics in response to iron and oxygen deprivation demonstrated an adaptive cellular response by mounting post-translational modifications that are critical for intracellular signaling and epigenetic programming in neuronal cells.
    Keywords:  HT22; hippocampal cells; hypoxia; iron deficiency; neuronal cells; oxygen sensing; phosphorylation; quantitative proteomics
    DOI:  https://doi.org/10.3390/nu13010179
  8. Sci Rep. 2021 Jan 14. 11(1): 1458
    Nastasi C, Willerlev-Olsen A, Dalhoff K, Ford SL, Gadsbøll AØ, Buus TB, Gluud M, Danielsen M, Litman T, Bonefeld CM, Geisler C, Ødum N, Woetmann A.
      T cell activation is intimately linked to metabolism, as distinct metabolic requirements support the functional and phenotypical differences between quiescent and activated T cells. Metabolic transition from mitochondrial oxidative phosphorylation to aerobic glycolysis is crucial for a proper T cell activation. However, the role of tricarboxylic acid cycle (TCA), and in particular succinate dehydrogenase (SDH) in activated T cells needs further elucidation. Here we show that inhibition of SDH during activation of T cells results in strong impairment of proliferation, expression of activation markers, and production of key inflammatory cytokines, despite a concomitant increase in glycolytic metabolic activity. Similar effect of SDH inhibition were demonstrated in pre-activated T cell. Interestingly, itaconic acid, an endogenous SDH inhibitor released from activated macrophages and dendritic cells, had no immunomodulator effect. Taken together, our findings demonstrate that SDH enzyme fitness is critical for mounting and maintaining appropriate activation and function of human T cells.
    DOI:  https://doi.org/10.1038/s41598-020-80933-7
  9. Cell Stem Cell. 2021 Jan 08. pii: S1934-5909(20)30593-2. [Epub ahead of print]
    Fang Y, Xu X, Ding J, Yang L, Doan MT, Karmaus PWF, Snyder NW, Zhao Y, Li JL, Li X.
      Histone crotonylation is a non-acetyl histone lysine modification that is as widespread as acetylation. However, physiological functions associated with histone crotonylation remain almost completely unknown. Here we report that histone crotonylation is crucial for endoderm differentiation. We demonstrate that key crotonyl-coenzyme A (CoA)-producing enzymes are specifically induced in endodermal cells during differentiation of human embryonic stem cells (hESCs) in vitro and in mouse embryos, where they function to increase histone crotonylation and enhance endodermal gene expression. Chemical enhancement of histone crotonylation promotes endoderm differentiation of hESCs, whereas deletion of crotonyl-CoA-producing enzymes reduces histone crotonylation and impairs meso/endoderm differentiation in vitro and in vivo. Our study uncovers a histone crotonylation-mediated mechanism that promotes endodermal commitment of pluripotent stem cells, which may have important implications for therapeutic strategies against a number of human diseases.
    Keywords:  crotonylation; embryogenesis; embryonic stem cells; endoderm differentiation; epigenetics; metabolic switch
    DOI:  https://doi.org/10.1016/j.stem.2020.12.009
  10. Free Radic Biol Med. 2021 Jan 12. pii: S0891-5849(21)00022-8. [Epub ahead of print]
    Sato T, Greco CM.
      Circadian rhythms play a central role in physiological and metabolic processes. This is mostly achieved through rhythmic regulation of myriad genes via dynamic epigenome changes. Accumulating evidence indicates that oxidative stress and redox balance are under circadian control and feedback on the clock system. Circadian perturbations induce oxidative stress accumulation and disturb redox balance. Along with these changes, epigenomic landscape changes are a remarkable hallmark of clock disruption. This review aims to summarize evidence supporting the link between the circadian clock and redox metabolism, focusing on possible connections through epigenetic mechanisms.
    Keywords:  circadian clock; epigenome landmark; histone modification; oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.01.009
  11. Int J Mol Sci. 2021 Jan 12. pii: E697. [Epub ahead of print]22(2):
    Wu KK.
      Cellular senescence contributes to aging and age-related disorders. High glucose (HG) induces mesenchymal stromal/stem cell (MSC) senescence, which hampers cell expansion and impairs MSC function. Intracellular HG triggers metabolic shift from aerobic glycolysis to oxidative phosphorylation, resulting in reactive oxygen species (ROS) overproduction. It causes mitochondrial dysfunction and morphological changes. Tryptophan metabolites such as 5-methoxytryptophan (5-MTP) and melatonin attenuate HG-induced MSC senescence by protecting mitochondrial integrity and function and reducing ROS generation. They upregulate the expression of antioxidant enzymes. Both metabolites inhibit stress-induced MSC senescence by blocking p38 MAPK signaling pathway, NF-κB, and p300 histone acetyltransferase activity. Furthermore, melatonin upregulates SIRT-1, which reduces NF-κB activity by de-acetylation of NF-κB subunits. Melatonin and 5-MTP are a new class of metabolites protecting MSCs against replicative and stress-induced cellular senescence. They provide new strategies to improve the efficiency of MSC-based therapy for diverse human diseases.
    Keywords:  5-methoxytryptophan; antioxidant enzymes; cellular senescence mitochondrial dysfunction; hyperglycemia; melatonin; mesenchymal stromal/stem cells; reactive oxygen species; type 2 diabetes
    DOI:  https://doi.org/10.3390/ijms22020697