bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2021‒06‒13
five papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Annu Rev Cancer Biol. 2021 Mar;5(1): 235-257
      Metabolic and epigenetic reprogramming are characteristics of cancer cells that, in many cases, are linked. Oncogenic signaling, diet, and tumor microenvironment each influence the availability of metabolites that are substrates or inhibitors of epigenetic enzymes. Reciprocally, altered expression or activity of chromatin-modifying enzymes can exert direct and indirect effects on cellular metabolism. In this article, we discuss the bidirectional relationship between epigenetics and metabolism in cancer. First, we focus on epigenetic control of metabolism, highlighting evidence that alterations in histone modifications, chromatin remodeling, or the enhancer landscape can drive metabolic features that support growth and proliferation. We then discuss metabolic regulation of chromatin-modifying enzymes and roles in tumor growth and progression. Throughout, we highlight proposed therapeutic and dietary interventions that leverage metabolic-epigenetic cross talk and have the potential to improve cancer therapy.
    Keywords:  cancer; cell metabolism; chromatin modification; epigenetics
  2. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2021 Feb 25. 50(1): 1-16
      Epigenetics concerns gene regulatory mechanisms beyond DNA sequence,such as DNA methylation,histone modification,chromatin remodeling,and non-coding RNA. Epigenetic mechanisms play a key role in development,cell fate decision and tumorigenesis. Chromatin modifications and its high order structure across our genome are major forms of epigenetic information,and its establishment and maintenance are closely related to cell metabolism. Metabolic changes in cancer cells include aerobic glycolysis,increased glucose uptake,abnormally active glutamine metabolism,and the use of non-conventional energy supply. These changes meet the vigorous energy and matter needs for the development and spread of cancer,and help tumor cells adapt to hypoxia microenvironment for their survival,proliferation,invasion and migration. There is a complex relationship between epigenetic modifications and cell metabolism in tumor. On the one hand,metabolites in tumor cells may act as cofactors,modification donors or antagonists of epigenetic enzymes,thus modulating the epigenetic landscape. On the other hand,epigenetic modifications can directly regulate the expression of metabolic enzymes,transporters,signaling pathway and transcription factors to affect cell metabolism. This article reviews the crosstalk between epigenetics and cancer metabolism,to explore their potential future applications in the treatment of tumors.
    Keywords:  DNA methylation; Epigenetic landscape; Epigenetics; Histone modification; Metabolism; Non-coding RNA; Review; Tumor
  3. Immunity. 2021 Jun 02. pii: S1074-7613(21)00223-5. [Epub ahead of print]
      Microbe-derived acetate activates the Drosophila immunodeficiency (IMD) pathway in a subset of enteroendocrine cells (EECs) of the anterior midgut. In these cells, the IMD pathway co-regulates expression of antimicrobial and enteroendocrine peptides including tachykinin, a repressor of intestinal lipid synthesis. To determine whether acetate acts on a cell surface pattern recognition receptor or an intracellular target, we asked whether acetate import was essential for IMD signaling. Mutagenesis and RNA interference revealed that the putative monocarboxylic acid transporter Tarag was essential for enhancement of IMD signaling by dietary acetate. Interference with histone deacetylation in EECs augmented transcription of genes regulated by the steroid hormone ecdysone including IMD targets. Reduced expression of the histone acetyltransferase Tip60 decreased IMD signaling and blocked rescue by dietary acetate and other sources of intracellular acetyl-CoA. Thus, microbe-derived acetate induces chromatin remodeling within enteroendocrine cells, co-regulating host metabolism and intestinal innate immunity via a Tip60-steroid hormone axis that is conserved in mammals.
    Keywords:  Drosophila melanogaster; IMD pathway; Tip60; Vibrio cholerae; acetate; ecdysone; ecdysone receptor; histone acetylation; histone acetyltransferase; innate immunity; intestinal microbiota; monocarboxylic acid transport
  4. Cell Mol Gastroenterol Hepatol. 2021 Jun 04. pii: S2352-345X(21)00114-4. [Epub ahead of print]
      BACKGROUND & AIMS: The pathogenesis of Wilson disease (WD) involves hepatic and brain copper accumulation due to pathogenic variants affecting the ATP7B gene and downstream epigenetic and metabolic mechanisms. Prior methylome investigations in human WD liver and blood and in the Jackson Laboratory C3He-Atp7btx-j/J (tx-j) WD mouse model revealed an epigenetic signature of WD, including changes in the histone deacetylase HDAC5. We tested the hypothesis that histone acetylation is altered with respect to copper overload and aberrant DNA methylation in WD.METHODS: We investigated class IIa histone deacetylases (HDAC4 and HDAC5) and H3K9/H3K27 histone acetylation in tx-j mouse livers compared to C3HeB/FeJ (C3H) control in response to 3 treatments: 60% kcal fat diet (HFD), D-penicillamine (PCA, copper chelator), and choline (methyl group donor). Experiments with copper-loaded HepG2 cells were conducted to validate in vivo studies.
    RESULTS: In 9-week tx-j mice, HDAC5 levels significantly increased after 8 days of HFD compared to chow. In 24-week tx-j mice, HDAC4/5 levels were reduced 5- to 10-fold compared to C3H, likely through mechanisms involving HDAC phosphorylation. HDAC4/5 levels were affected by disease progression and accompanied by increased acetylation. PCA and choline partially restored HDAC4/5 and H3K9ac/H3K27ac to C3H levels. Integrated RNA and chromatin immunoprecipitation sequencing analyses revealed genes regulating energy metabolism and cellular stress/development which were, in turn, regulated by histone acetylation in tx-j mice compared to C3H, with Pparα and Pparγ among the most relevant targets.
    CONCLUSION: These results suggest dietary modulation of class IIa HDAC4/5, and subsequent H3K9/H3K27 acetylation/deacetylation, can regulate gene expression in key metabolic pathways in the pathogenesis of WD.
    Keywords:  copper; histone deacetylase; liver; metabolism
  5. Development. 2021 Jun 01. pii: dev199609. [Epub ahead of print]148(11):
      The intimate relationships between cell fate and metabolism have long been recognized, but a mechanistic understanding of how metabolic pathways are dynamically regulated during development and disease, how they interact with signalling pathways, and how they affect differential gene expression is only emerging now. We summarize the key findings and the major themes that emerged from the virtual Keystone Symposium 'Metabolic Decisions in Development and Disease' held in March 2021.
    Keywords:  Cell fate; Development; Metabolic plasticity; Metabolism; Nutrition