bims-meprid 2020-10-04 papers

Issue of 2020‒10‒04
four papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

J Biomed Res. 2020 Aug 06. 1-11

α-ketoglutarate promotes the specialization of primordial germ cell-like cells through regulating epigenetic reprogramming.

Ming Xing, Na Wang, Hanyi Zeng, Jun Zhang.

There is growing evidence that cellular metabolism can directly participate in epigenetic dynamics and consequently modulate gene expression. However, the role of metabolites in activating the key gene regulatory network for specialization of germ cell lineage remains largely unknown. Here, we identified some cellular metabolites with significant changes by untargeted metabolomics between mouse epiblast-like cells (EpiLCs) and primordial germ cell-like cells (PGCLCs). More importantly, we found that inhibition of glutaminolysis by bis-2- (5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) impeded PGCLC specialization, but the impediment could be rescued by addition of α-ketoglutarate (αKG), the intermediate metabolite of oxidative phosphorylation and glutaminolysis. Moreover, adding αKG alone to the PGCLC medium accelerated the PGCLC specialization through promoting H3K27me3 demethylation. Thus, our study reveals the importance of metabolite αKG in the germ cell fate determination and highlights the essential role of cellular metabolism in shaping the cell identities through epigenetic events.

Keywords: cellular metabolism; epigenome; primordial germ cells; α-ketoglutarate

DOI: https://doi.org/10.7555/JBR.34.20190160

Mol Neurobiol. 2020 Oct 02.

Metabolic Flexibility Assists Reprograming of Central and Peripheral Innate Immunity During Neurodevelopment.

Gabriela Cruz-Carrillo, Alberto Camacho-Morales.

Central innate immunity assists time-dependent neurodevelopment by recruiting and interacting with peripheral immune cells. Microglia are the major player of central innate immunity integrating peripheral signals arising from the circumventricular regions lacking the blood-brain barrier (BBB), via neural afferent pathways such as the vagal nerve and also by choroid plexus into the brain ventricles. Defective and/or unrestrained activation of central and peripheral immunity during embryonic development might set an aberrant connectome establishment and brain function, leading to major psychiatric disorders in postnatal stages. Molecular candidates leading to central and peripheral innate immune overactivation identified metabolic substrates and lipid species as major contributors of immunological priming, supporting the role of a metabolic flexibility node during trained immunity. Mechanistically, trained immunity is established by an epigenetic program including DNA methylation and histone acetylation, as the major molecular epigenetic signatures to set immune phenotypes. By definition, immunological training sets reprogramming of innate immune cells, enhancing or repressing immune responses towards a second challenge which potentially might contribute to neurodevelopment disorders. Notably, the innate immune training might be set during pregnancy by maternal immune activation stimuli. In this review, we integrate the most valuable scientific evidence supporting the role of metabolic cues assisting metabolic flexibility, leading to innate immune training during development and its effects on aberrant neurological phenotypes in the offspring. We also add reports supporting the role of methylation and histone acetylation signatures as a major epigenetic mechanism regulating immune training.

Keywords: Epigenetics; Inflammation; Maternal programming; Methylation; Transgenerational heritance

DOI: https://doi.org/10.1007/s12035-020-02154-3

Biochem Soc Trans. 2020 Sep 28. pii: BST20190333. [Epub ahead of print]

Human 2-oxoglutarate-dependent oxygenases: nutrient sensors, stress responders, and disease mediators.

Sally C Fletcher, Mathew L Coleman.

Fe(II)/2-oxoglutarate (2OG)-dependent oxygenases are a conserved enzyme class that catalyse diverse oxidative reactions across nature. In humans, these enzymes hydroxylate a broad range of biological substrates including DNA, RNA, proteins and some metabolic intermediates. Correspondingly, members of the 2OG-dependent oxygenase superfamily have been linked to fundamental biological processes, and found dysregulated in numerous human diseases. Such findings have stimulated efforts to understand both the biochemical activities and cellular functions of these enzymes, as many have been poorly studied. In this review, we focus on human 2OG-dependent oxygenases catalysing the hydroxylation of protein and polynucleotide substrates. We discuss their modulation by changes in the cellular microenvironment, particularly with respect to oxygen, iron, 2OG and the effects of oncometabolites. We also describe emerging evidence that these enzymes are responsive to cellular stresses including hypoxia and DNA damage. Moreover, we examine how dysregulation of 2OG-dependent oxygenases is associated with human disease, and the apparent paradoxical role for some of these enzymes during cancer development. Finally, we discuss some of the challenges associated with assigning biochemical activities and cellular functions to 2OG-dependent oxygenases.

Keywords: disease; hydroxylation; hypoxia; nutrient sensing; oxygenase; post translational modification

DOI: https://doi.org/10.1042/BST20190333

FASEB J. 2020 Sep 30.

Metabolism of short-chain fatty acid propionate induces surface expression of NKG2D ligands on cancer cells.

Rikke Illum Høgh, Sofie Hedlund Møller, Stine Dam Jepsen, Maiken Mellergaard, Astrid Lund, Mikala Pejtersen, Emil Fitzner, Lars Andresen, Søren Skov.

SCFAs are primarily produced in the colon by bacterial fermentation of nondigestible carbohydrates. Besides providing energy, SCFAs can suppress development of colon cancer. The mechanism, however, remains elusive. Here, we demonstrate that the SCFA propionate upregulates surface expression of the immune stimulatory NKG2D ligands, MICA/B by imposing metabolic changes in dividing cells. Propionate-mediated MICA/B expression did not rely on GPR41/GPR43 receptors but depended on functional mitochondria. By siRNA-directed knockdown, we could further link phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme in gluconeogenesis to propionate regulation of MICA/B expression. Moreover, knockdown of Rictor and specific mTOR inhibitors implicated mTORC2 activity with metabolic changes that control MICA/B expression. SCFAs are precursors to short-chain acyl-CoAs that are used for histone acylation thereby linking the metabolic state to chromatin structure and gene expression. Propionate increased the overall acetylation and propionylation and inhibition of lysine acetyltransferases (KATs) that are responsible for adding acyl-CoAs to histones reduced propionate-mediated MICA/B expression, suggesting that propionate-induced acylation increases MICA/B expression. Notably, propionate upregulated MICA/B surface expression on colon cancer cells in an acylation-dependent manner; however, the impact of mitochondrial metabolism on MICA/B expression was different in colon cancer cells compared with Jurkat cells, suggesting that continuous exposure to propionate in the colon may provide an enhanced capacity to metabolize propionate. Together, our findings support that propionate causes metabolic changes resulting in NKG2D ligand surface expression, which holds potential as an immune activating anticancer therapy.

Keywords: NKG2D ligands; cancer; immunometabolism; short-chain fatty acids

DOI: https://doi.org/10.1096/fj.202000162R