bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2021‒08‒08
five papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Cell Rep. 2021 Aug 03. pii: S2211-1247(21)00914-1. [Epub ahead of print]36(5): 109487
      Ketone bodies are bioactive metabolites that function as energy substrates, signaling molecules, and regulators of histone modifications. β-hydroxybutyrate (β-OHB) is utilized in lysine β-hydroxybutyrylation (Kbhb) of histones, and associates with starvation-responsive genes, effectively coupling ketogenic metabolism with gene expression. The emerging diversity of the lysine acylation landscape prompted us to investigate the full proteomic impact of Kbhb. Global protein Kbhb is induced in a tissue-specific manner by a variety of interventions that evoke β-OHB. Mass spectrometry analysis of the β-hydroxybutyrylome in mouse liver revealed 891 sites of Kbhb within 267 proteins enriched for fatty acid, amino acid, detoxification, and one-carbon metabolic pathways. Kbhb inhibits S-adenosyl-L-homocysteine hydrolase (AHCY), a rate-limiting enzyme of the methionine cycle, in parallel with altered metabolite levels. Our results illuminate the role of Kbhb in hepatic metabolism under ketogenic conditions and demonstrate a functional consequence of this modification on a central metabolic enzyme.
    Keywords:  AHCY; S-adenosyl-L-homocysteine hydrolase; ketogenesis; ketogenic diet; liver metabolism; lysine acylation; methionine cycle; β-hydroxybutyrate; β-hydroxybutyrylation
  2. Front Mol Biosci. 2021 ;8 682696
      Studies indicate that induction of metabolic gene expression by nutrient intake, and in response to subsequently secreted hormones, is regulated by transcription factors binding to cis-elements and associated changes of epigenetic memories (histone modifications and DNA methylation) located in promoter and enhancer regions. Carbohydrate intake-mediated induction of metabolic gene expression is regulated by histone acetylation and the histone acetylation reader bromodomain-containing protein 4 (BRD4) on the gene body region, which corresponds to the transcribed region of the gene. In this review, we introduce carbohydrate-responsive metabolic gene regulation by (i) transcription factors and epigenetic memory in promoter/enhancer regions (promoter/enhancer-based epigenetics), and (ii) histone acetylation and BRD4 in the gene body region (gene body-based epigenetics). Expression of carbohydrate-responsive metabolic genes related to nutrient digestion and absorption, fat synthesis, inflammation in the small intestine, liver and white adipose tissue, and in monocytic/macrophage-like cells are regulated by various transcription factors. The expression of these metabolic genes are also regulated by transcription elongation via histone acetylation and BRD4 in the gene body region. Additionally, the expression of genes related to fat synthesis, and the levels of acetylated histones and BRD4 in fat synthesis-related genes, are downregulated in white adipocytes under insulin resistant and/or diabetic conditions. In contrast, expression of carbohydrate-responsive metabolic genes and/or histone acetylation and BRD4 binding in the gene body region of these genes, are upregulated in the small intestine, liver, and peripheral leukocytes (innate leukocytes) under insulin resistant and/or diabetic conditions. In conclusion, histone acetylation and BRD4 binding in the gene body region as well as transcription factor binding in promoter/enhancer regions regulate the expression of carbohydrate-responsive metabolic genes in many metabolic organs. Insulin resistant and diabetic conditions induce the development of metabolic diseases, including type 2 diabetes, by reducing the expression of BRD4-targeted carbohydrate-responsive metabolic genes in white adipose tissue and by inducing the expression of BRD4-targeted carbohydrate-responsive metabolic genes in the liver, small intestine, and innate leukocytes including monocytes/macrophages and neutrophils.
    Keywords:  BRD4; carbohydrate; gene body-epigenetics; histone acetylation; metabolic diseases; transcriptional elongation reaction; type 2 diabetes
  3. Cell. 2021 Aug 05. pii: S0092-8674(21)00838-2. [Epub ahead of print]184(16): 4109-4112
      Interplay between metabolic and epigenetic remodeling may be key to cell fate control. In this issue of Cell, Puleston et al. and Wagner et al. use metabolomic, computational, and genetic approaches to uncover that polyamine metabolism directs T helper cell lineage choices, epigenetic state, and pathogenic potential in inflammation.
  4. Biomedicines. 2021 Jul 10. pii: 799. [Epub ahead of print]9(7):
      Discovery of point mutations in the genes encoding isocitrate dehydrogenases (IDH) in gliomas about a decade ago has challenged our view of the role of metabolism in tumor progression and provided a new stratification strategy for malignant gliomas. IDH enzymes catalyze the conversion of isocitrate to alpha-ketoglutarate (α-KG), an intermediate in the citric acid cycle. Specific mutations in the genes encoding IDHs cause neomorphic enzymatic activity that produces D-2-hydroxyglutarate (2-HG) and result in the inhibition of α-KG-dependent enzymes such as histone and DNA demethylases. Thus, chromatin structure and gene expression profiles in IDH-mutant gliomas appear to be different from those in IDH-wildtype gliomas. IDH mutations are highly common in lower grade gliomas (LGG) and secondary glioblastomas, and they are among the earliest genetic events driving tumorigenesis. Therefore, inhibition of mutant IDH enzymes in LGGs is widely accepted as an attractive therapeutic strategy. On the other hand, the metabolic consequences derived from IDH mutations lead to selective vulnerabilities within tumor cells, making them more sensitive to several therapeutic interventions. Therefore, instead of shutting down mutant IDH enzymes, exploiting the selective vulnerabilities caused by them might be another attractive and promising strategy. Here, we review therapeutic options and summarize current preclinical and clinical studies on IDH-mutant gliomas.
    Keywords:  clinical trials; glioblastoma; glioma; isocitrate dehydrogenase (IDH); mutations; therapeutics
  5. Physiol Rep. 2021 Aug;9(15): e14965
      Protein posttranslational modifications (PTMs) by O-linked β-N-acetylglucosamine (O-GlcNAc) rise during pressure-overload hypertrophy (POH) to affect hypertrophic growth. The hexosamine biosynthesis pathway (HBP) branches from glycolysis to make the moiety for O-GlcNAcylation. It is speculated that greater glucose utilization during POH augments HBP flux to increase O-GlcNAc levels; however, recent results suggest glucose availability does not primarily regulate cardiac O-GlcNAc levels. We hypothesize that induction of key enzymes augment protein O-GlcNAc levels primarily during active myocardial hypertrophic growth and remodeling with early pressure overload. We further speculate that downregulation of protein O-GlcNAcylation inhibits ongoing hypertrophic growth during prolonged pressure overload with established hypertrophy. We used transverse aortic constriction (TAC) to create POH in C57/Bl6 mice. Experimental groups were sham, 1-week TAC (1wTAC) for early hypertrophy, or 6-week TAC (6wTAC) for established hypertrophy. We used western blots to determine O-GlcNAc regulation. To assess the effect of increased protein O-GlcNAcylation with established hypertrophy, mice received thiamet-g (TG) starting 4 weeks after TAC. Protein O-GlcNAc levels were significantly elevated in 1wTAC versus Sham with a fall in 6wTAC. OGA, which removes O-GlcNAc from proteins, fell in 1wTAC versus sham. GFAT is the rate-limiting HBP enzyme and the isoform GFAT1 substantially rose in 1wTAC. With established hypertrophy, TG increased protein O-GlcNAc levels but did not affect cardiac mass. In summary, protein O-GlcNAc levels vary during POH with elevations occurring during active hypertrophic growth early after TAC. O-GlcNAc levels appear to be regulated by changes in key enzyme levels. Increasing O-GlcNAc levels during established hypertrophy did not restart hypertrophic growth.
    Keywords:  Cardiac hypertrophy; GFAT; O-GlcNAc; glucose metabolism; hexosamine biosynthesis pathway; pressure-overload hypertrophy; thiamet-g; transverse aortic constriction