bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2021‒07‒18
nine papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Adv Exp Med Biol. 2021 ;1332 1-15
      Amino acids have pleiotropic roles in animal biology including protein and glucose synthesis, cellular metabolism, antioxidant reactions, immune enhancers, and inducers or suppressors of gene expression. Recent studies have revealed important roles of amino acids in the regulation of gene expression in animals. Discoveries of cellular amino acid sensors and their mechanistic pathways have broadened our understanding of how the body responds to the deprivation of nutrients and amino acids in particular. Alterations in concentrations of extracellular amino acids can modulate transcription, translation, posttranscriptional modifications, and epigenetic regulation of genes and proteins. Cells have intracellular amino acid sensors, for example, Sestrin2 for leucine and CASTOR2 for arginine, that respond to sufficiency or deficiency in amino acids, thereby inhibiting or activating downstream signals for gene expression, respectively. The sufficiency of an amino acid in cells ensures its binding to cognate sensors and suppression of inhibitors of MTOR, leading to increased global protein synthesis. On the other hand, deprivation of amino acids activates the amino acid response pathway (GCN2-eIF2a-ATF4), leading to increased selective translation of the activating transcription factor 4 (ATF4). Deficiency of an amino acid itself or via the action of ATF4 suppression of MTORC1 activity limits global protein synthesis. ATF4, in response to low concentrations of cellular amino acids, mediates the transcription of groups of genes such as those for amino acid transport and biosynthesis (ASNS, CAT-1, SNAT2), autophagy (ATG3, ATG10, ATG12), and serine-glycine synthesis (PHGDH, PSAT1, PSPH, MTHFD2). Long-term amino acid starvation has a pronounced effect on cells: suppressed expression and translation of genes required for normal cell growth and metabolism and enhanced expression of genes required for cell adaptation and survival. Levels of amino acids also affect the posttranslational modifications of proteins through mechanisms such as acetylation, ADP-ribosylation, disulfide bond formation, glutamylation, and hydroxylation.
    Keywords:  ATF4; Amino acids; Gene expression; MTOR; Protein synthesis
  2. J Bacteriol. 2021 Jul 12. JB0023121
      Protein lysine acetylation is a conserved post-translational modification that modulates several cellular processes. Protein acetylation and its physiological implications are well understood in eukaryotes; however, its role is emerging in bacteria. Lysine acetylation in bacteria is fine-tuned by the concerted action of lysine acetyltransferases (KATs), protein deacetylases (KDACs), metabolic intermediates- acetyl-coenzyme A (Ac-CoA) and acetyl phosphate (AcP). AcP mediated nonenzymatic acetylation is predominant in bacteria due to its high acetyl transfer potential whereas, enzymatic acetylation by bacterial KATs (bKAT) are considered less abundant. SePat, the first bKAT discovered in Salmonella enterica, regulates the activity of the central metabolic enzyme- acetyl-CoA synthetase, through its acetylation. Recent studies have highlighted the role of bKATs in stress responses like pH tolerance, nutrient stress, persister cell formation, antibiotic resistance and pathogenesis. Bacterial genomes encode many putative bKATs of unknown biological function and significance. Detailed characterization of putative and partially characterized bKATs is important to decipher the acetylation mediated regulation in bacteria. Proper synthesis of information about the diverse roles of bKATs is missing to date, which can lead to the discovery of new antimicrobial targets in future. In this review, we provide an overview of the diverse physiological roles of known bKATs, and their mode of regulation in different bacteria. We also highlight existing gaps in the literature and present questions that may help understand the regulatory mechanisms mediated by bKATs in adaptation to a diverse habitat.
  3. Endocr J. 2021 Jul 15.
      α-Ketoglutarate (α-KG) also known as 2-oxoglutarate (2-OG) is an intermediate metabolite in the tricarboxylic acid (TCA) cycle and is also produced by the deamination of glutamate. It is an indispensable cofactor for a series of 2-oxoglutarate-dependent oxygenases including epigenetic modifiers such as ten-eleven translocation DNA demethylases (TETs) and JmjC domain-containing histone demethylases (JMJDs). Since these epigenetic enzymes target genomic DNA and histone in the nucleus, the nuclear concentration of α-KG would affect the levels of transcription by modulating the activity of the epigenetic enzymes. Thus, it is of great interest to measure the nuclear concentration of α-KG to elucidate the regulatory mechanism of these enzymes. Here, we report a novel fluorescence resonance energy transfer (FRET)-based biosensor with multiple nuclear localization signals (NLSs) to measure the nuclear concentration of α-KG. The probe contains the α-KG-binding GAF domain of NifA protein from Azotobacter vinelandii fused with EYFP and ECFP. Treatment of 3T3-L1 preadipocytes expressing this probe with either dimethyl-2-oxoglutarate (dimethyl-2-OG), a cell-permeable 2-OG derivative, or citrate elicited time- and dose-dependent changes in the FRET ratio, proving that this probe functions as an α-KG sensor. Measurement of the nuclear α-KG levels in the 3T3-L1 cells stably expressing the probe during adipocyte differentiation revealed that the nuclear concentration of α-KG increased in the early stage of differentiation and remained high thereafter. Thus, this nuclear-localized α-KG probe is a powerful tool for real-time monitoring of α-KG concentrations with subcellular resolution in living cells and is useful for elucidating the regulatory mechanisms of epigenetic enzymes.
    Keywords:  Adipocyte differentiation; Fluorescence resonance energy transfer; Nuclear probe; Subcellular concentration; α-Ketoglutarate
  4. Front Genet. 2021 ;12 650863
      Background: The number of diet induced obese population is increasing every year, and the incidence of type 2 diabetes is also on the rise. Histone methylation and acetylation have been shown to be associated with lipogenesis and obesity by manipulating gene expression via the formation of repression or activation domains on chromosomes.Objective: In this study, we aimed to explore gene activation or repression and related biological processes by histone modification across the whole genome on a high-fat diet (HFD) condition. We also aimed to elucidate the correlation of these genes that modulated by histone modification with energy metabolism and inflammation under both short-term and long-term HFD conditions.
    Method: We performed ChIP-seq analysis of H3K9me2 and H3K9me3 in brown and white adipose tissues (WATs; subcutaneous adipose tissue) from mice fed with a standard chow diet (SCD) or HFD and a composite analysis of the histone modification of H3K9me2, H3K9me3, H3K4me1 and H3K27ac throughout the whole genome. We also employed and integrated two bulk RNA-seq and a single-nuclei RNA sequencing dataset and performed western blotting (WB) to confirm the gene expression levels in adipose tissue of the SCD and HFD groups.
    Results: The ChIP-seq and transcriptome analysis of mouse adipose tissues demonstrated that a series of genes were activated by the histone modification of H3K9me2, H3K9me3, H3K4me1, and H3K27ac in response to HFD condition. These genes were enriched in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in lipogenesis, energy metabolism and inflammation. Several genes in the activated mitogen-activated protein kinase (MAPK) pathway might be related to both inflammation and energy metabolism in mice, rats and humans fed with HFD for a short or long term, as showed by bulk RNA-seq and single nuclei RNA-seq datasets. Western blot analyses further confirmed the increased expression of MET, VEGFA and the enhanced phosphorylation ratio of p44/42 MAPK upon HFD treatment.
    Conclusion: This study expanded our understanding of the influence of eating behavior on obesity and could assist the identification of putative therapeutic targets for the prevention and treatment of metabolic disorders in the future.
    Keywords:  adipose tissue; epigenetics; high-fat diet; inflammation; methylation; obesity
  5. Curr Stem Cell Res Ther. 2021 Jul 14.
      Emerging evidence suggests that ascorbic acid (vitamin C) enhances the reprogramming process by multiple mechanisms. This is primarily due to its cofactor role in Fe(II) and 2-oxoglutarate-dependent dioxygenases, including the DNA demethylases Ten Eleven Translocase (TET) and histone demethylases. Epigenetic variations have been shown to play a critical role in somatic cell reprogramming. DNA methylation and histone methylation are extensively recognized as barriers to somatic cell reprogramming. N6-methyladenosine (m6A), known as RNA methylation, is an epigenetic modification of mRNAs and has also been shown to play a role in regulating cellular reprogramming. Multiple cofactors are reported to promote the activity of demethylases, including vitamin C. This review focuses on examining the evidence and mechanism of vitamin C in DNA and histone demethylation and highlights its potential involvement in regulating m6A demethylation. It also shows the significant contribution of vitamin C in epigenetic regulation and the affiliation of demethylases with vitamin C-facilitated epigenetic reprogramming.
    Keywords:  DNA demethylation; RNA demethylation; Vitamin C; histone demethylation; iron and 2-oxoglutarate dependent dioxygenases; reprogramming; somatic cell regeneration
  6. Ann Transl Med. 2021 May;9(9): 758
      Background: The purpose of this study was to determine whether elevated glucose can induce a dermal microvascular endothelial cell metabolic memory, thus affecting angiogenesis in the repair process of mammalian cutaneous wound. We hypothesized that transient elevated glucose levels cause sustained alteration of endothelial cell responses to injury and persistent epigenetic changes in gene expression.Methods: Human dermal microvascular endothelial cells were exposed to experimental conditions with or without 30 mM D-glucose. The control group was maintained at 5 mM D-glucose; while in the transient glucose group, after being exposed to 30 mM D-glucose for two days, then being put under the control conditions during the experiment. Besides, in the whole process of the experiment, the chronic glucose group was kept in the condition with 30 mM D-glucose. Proliferation, migration, tube formation, gene expression and histone methylation were assessed for individual conditions.
    Results: Transient elevated glucose caused sustained effects on endothelial cell migration, tube formation and TIMP3 gene expression. The effects on TIMP3 expression were associated with persistent changes in histone modification at the 5' end of the TIMP3 gene, suggesting an epigenetic effect.
    Conclusions: Hyperglycemia induced metabolic memory could promote the regulation of TIMP3, and it can be used as a possible innovative molecular target for therapeutic intervention in the treatment of chronic non-healing diabetic wounds.
    Keywords:  Diabetes; angiogenesis; epigenetics; hyperglycemia; metabolic memory
  7. Environ Pollut. 2021 Sep 01. pii: S0269-7491(21)01100-3. [Epub ahead of print]284 117518
      Perfluorooctane sulfonate (PFOS), an artificial perfluorinated compound, has been associated with male reproductive disorders. Histone modifications are important epigenetic mediators; however, the impact of PFOS exposure on testicular steroidogenesis through histone modification regulations remains to be elucidated. In this study, we examined the roles of histone modifications in regulating steroid hormone production in male rats chronically exposed to low-level PFOS. The results indicate that PFOS exposure significantly up-regulated the expressions of StAR, CYP11A1 and 3β-HSD, while CYP17A1 and 17β-HSD were down-regulated, thus contributing to the elevated progesterone and testosterone levels. Furthermore, PFOS significantly increased the histones H3K9me2, H3K9ac and H3K18ac while reduced H3K9me3 in rat testis. It is known that histone modifications are closely involved in gene transcription. Therefore, to investigate the association between histone modifications and steroidogenic gene regulation, the levels of these histone marks were further measured in steroidogenic gene promoter regions by ChIP. It was found that H3K18ac was augmented in Cyp11a1 promoter, and H3K9ac was increased in Hsd3b after PFOS exposure, which is proposed to result in the activation of CYP11A1 and 3β-HSD, respectively. To sum up, chronic low-level PFOS exposure activated key steroidogenic gene expression through enhancing histone acetylation (H3K9ac and H3K18ac), ultimately stimulating steroid hormone biosynthesis in rat testis.
    Keywords:  Histone acetylation; Low-dose exposure; Perfluorooctane sulfonate; Steroidogenic stimulation; Testicular steroidogenesis
  8. Semin Perinatol. 2021 Jun 17. pii: S0146-0005(21)00069-0. [Epub ahead of print] 151455
      The interaction between the gut and its eventual trillions of microbe inhabitants during microbial colonization, represents a critical time period for establishing the overall health and wellbeing of an individual. The gut microbiome represents a diverse community of microbes that are critical for many physiological roles of the host including host metabolism. These processes are controlled by a fine-tuned chemical cross talk between the host and microbiota. Although the exact mechanisms behind this cross talk remains elusive, microbiota induced epigenetic mechanisms like DNA methylation and histone modifications may be key. This review presents our perspective on the epigenome as a mediator for host-microbiota cross talk, as well as methodology to study epigenetics, the role of dysbiosis in disease, and how the gut microbiome-host axis may be used in personal medicine.
    Keywords:  cancer; disease; dna methylation; dysbiosis; epigenetics; epigenome; gut; inflammatory bowel disease; microbiome; necrotizing enterocolitis
  9. Cell Rep. 2021 Jul 13. pii: S2211-1247(21)00759-2. [Epub ahead of print]36(2): 109361
      Mouse embryonic stem cell (ESC) pluripotency is tightly regulated by a complex network composed of extrinsic and intrinsic factors that allow proper organismal development. O-linked β-N-acetylglucosamine (O-GlcNAc) is the sole glycosylation mark found on cytoplasmic and nuclear proteins and plays a pivotal role in regulating fundamental cellular processes; however, its function in ESC pluripotency is still largely unexplored. Here, we identify O-GlcNAcylation of proteasome activator subunit 3 (Psme3) protein as a node of the ESC pluripotency network. Mechanistically, O-GlcNAc modification of serine 111 (S111) of Psme3 promotes degradation of Ddx6, which is essential for processing body (P-body) assembly, resulting in the maintenance of ESC pluripotent state. Conversely, loss of Psme3 S111 O-GlcNAcylation stabilizes Ddx6 and increases P-body levels, culminating in spontaneous exit of ESC from the pluripotent state. Our findings establish O-GlcNAcylation at S111 of Psme3 as a switch that regulates ESC pluripotency via control of P-body homeostasis.
    Keywords:  Ddx6; O-GlcNAc; P-bodies; PA28γ; Psme3; embryonic stem cells; glycosylation; phase separation; pluripotency; proteasome