bims-meprid 2021-05-16 papers

Issue of 2021‒05‒16
five papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

Mol Metab. 2021 May 11. pii: S2212-8778(21)00094-6. [Epub ahead of print] 101249

Histone H3K9 butyrylation is regulated by dietary fat and stress via an acyl-CoA dehydrogenase short chain-dependent mechanism.

Zhi Yang, Minzhen He, Julianne Austin, Jessica Pfleger, Maha Abdellatif.

OBJECTIVE: We previously reported that β-oxidation enzymes are present in the nucleus in close proximity to transcriptionally active promoters. Thus, we hypothesized that the fatty acid intermediate, butyryl-CoA, is the substrate for histone butyrylation and its abundance is regulated by acyl-CoA dehydrogenase short chain (ACADS). The objective of this study was to determine the genomic distribution of H3K9-butyryl (H3K9Bu) and its regulation by dietary fat, stress, and ACADS, and its correlation with gene expression under these conditions.METHODS AND RESULTS: Using genome-wide chromatin immunoprecipitation-sequencing (ChIP-Seq), we show that H3K9Bu is abundant at all transcriptionally active promoters, where, paradoxically, it is most enriched in mice fed a fat-free versus a high-fat diet. Deletion of fatty acid synthetase (FASN) abolished H3K9Bu in cells maintained in a glucose-rich, but not fatty acid-rich, medium, signifying that fatty acid synthesis from carbohydrates substitutes for dietary fat as a source butyryl-CoA. Meanwhile, a high-fat diet induced an increase in ACADS expression that accompanied the decrease in H3K9Bu. Conversely, deletion of ACADS increased H3K9Bu in human cells and mouse hearts, and reversed high-fat- and stress-induced reduction in promoter-H3K9Bu, whose abundance coincided with diminished stress-regulated gene expression, as revealed by RNA-sequencing. In contrast, H3K9-acetyl (H3K9Ac) abundance was minimally impacted by diet.
CONCLUSION: Promoter H3K9 butyrylation is a major histone modification, which is negatively regulated by high-fat and stress in an ACADS-dependent fashion, and moderates stress-regulated gene expression.

DOI: https://doi.org/10.1016/j.molmet.2021.101249

J Allergy Clin Immunol. 2021 May 06. pii: S0091-6749(21)00555-8. [Epub ahead of print]

CD4+ T-cell differentiation and function: Unifying glycolysis, fatty acid oxidation, polyamines NAD mitochondria.

Luís Almeida, Ayesha Dhillon-LaBrooy, Guilhermina Carriche, Luciana Berod, Tim Sparwasser.

The progression through different steps of T-cell development, activation, and effector function is tightly bound to specific cellular metabolic processes. Previous studies established that T-effector cells have a metabolic bias toward aerobic glycolysis, whereas naive and regulatory T cells mainly rely on oxidative phosphorylation. More recently, the field of immunometabolism has drifted away from the notion that mitochondrial metabolism holds little importance in T-cell activation and function. Of note, T cells possess metabolic promiscuity, which allows them to adapt their nutritional requirements according to the tissue environment. Altogether, the integration of these metabolic pathways culminates in the generation of not only energy but also intermediates, which can regulate epigenetic programs, leading to changes in T-cell fate. In this review, we discuss the recent literature on how glycolysis, amino acid catabolism, and fatty acid oxidation work together with the tricarboxylic acid cycle in the mitochondrion. We also emphasize the importance of the electron transport chain for T-cell immunity. We also discuss novel findings highlighting the role of key enzymes, accessory pathways, and posttranslational protein modifications that distinctively regulate T-cell function and might represent prominent candidates for therapeutic purposes.

Keywords: CD4; T cell; antibiotics; arginine; fatty acid oxidation; immunometabolism; metabolism; mitochondria; polyamine

DOI: https://doi.org/10.1016/j.jaci.2021.03.033

Nat Metab. 2021 May 10.

Cell-surface SLC nucleoside transporters and purine levels modulate BRD4-dependent chromatin states.

Kai-Chun Li, Enrico Girardi, Felix Kartnig, Sarah Grosche, Tea Pemovska, Johannes W Bigenzahn, Ulrich Goldmann, Vitaly Sedlyarov, Ariel Bensimon, Sandra Schick, Jung-Ming G Lin, Bettina Gürtl, Daniela Reil, Kristaps Klavins, Stefan Kubicek, Sara Sdelci, Giulio Superti-Furga.

Metabolism negotiates cell-endogenous requirements of energy, nutrients and building blocks with the immediate environment to enable various processes, including growth and differentiation. While there is an increasing number of examples of crosstalk between metabolism and chromatin, few involve uptake of exogenous metabolites. Solute carriers (SLCs) represent the largest group of transporters in the human genome and are responsible for the transport of a wide variety of substrates, including nutrients and metabolites. We aimed to investigate the possible involvement of SLC-mediated solutes uptake and cellular metabolism in regulating cellular epigenetic states. Here, we perform a CRISPR-Cas9 transporter-focused genetic screen and a metabolic compound library screen for the regulation of BRD4-dependent chromatin states in human myeloid leukaemia cells. Intersection of the two orthogonal approaches reveal that loss of transporters involved with purine transport or inhibition of de novo purine synthesis lead to dysfunction of BRD4-dependent transcriptional regulation. Through mechanistic characterization of the metabolic circuitry, we elucidate the convergence of SLC-mediated purine uptake and de novo purine synthesis on BRD4-chromatin occupancy. Moreover, adenine-related metabolite supplementation effectively restores BRD4 functionality on purine impairment. Our study highlights the specific role of purine/adenine metabolism in modulating BRD4-dependent epigenetic states.

DOI: https://doi.org/10.1038/s42255-021-00386-8

Cell Rep. 2021 May 11. pii: S2211-1247(21)00435-6. [Epub ahead of print]35(6): 109101

Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation.

Depleting the microenvironment of important nutrients such as arginine is a key strategy for immune evasion by cancer cells. Many tumors overexpress arginase, but it is unclear how these cancers, but not T cells, tolerate arginine depletion. In this study, we show that tumor cells synthesize arginine from citrulline by upregulating argininosuccinate synthetase 1 (ASS1). Under arginine starvation, ASS1 transcription is induced by ATF4 and CEBPβ binding to an enhancer within ASS1. T cells cannot induce ASS1, despite the presence of active ATF4 and CEBPβ, as the gene is repressed. Arginine starvation drives global chromatin compaction and repressive histone methylation, which disrupts ATF4/CEBPβ binding and target gene transcription. We find that T cell activation is impaired in arginine-depleted conditions, with significant metabolic perturbation linked to incomplete chromatin remodeling and misregulation of key genes. Our results highlight a T cell behavior mediated by nutritional stress, exploited by cancer cells to enable pathological immune evasion.

Keywords: ASS1; ATF4; H3K27me3; T cell chromatin; arginine; cancer metabolism; immunometabolism; immunosuppression; metabolic regulation; nutritional stress

DOI: https://doi.org/10.1016/j.celrep.2021.109101

Front Cell Dev Biol. 2021 ;9 654337

Interplay Between Glucose Metabolism and Chromatin Modifications in Cancer.

Rui Ma, Yinsheng Wu, Shanshan Li, Xilan Yu.

Cancer cells reprogram glucose metabolism to meet their malignant proliferation needs and survival under a variety of stress conditions. The prominent metabolic reprogram is aerobic glycolysis, which can help cells accumulate precursors for biosynthesis of macromolecules. In addition to glycolysis, recent studies show that gluconeogenesis and TCA cycle play important roles in tumorigenesis. Here, we provide a comprehensive review about the role of glycolysis, gluconeogenesis, and TCA cycle in tumorigenesis with an emphasis on revealing the novel functions of the relevant enzymes and metabolites. These functions include regulation of cell metabolism, gene expression, cell apoptosis and autophagy. We also summarize the effect of glucose metabolism on chromatin modifications and how this relationship leads to cancer development. Understanding the link between cancer cell metabolism and chromatin modifications will help develop more effective cancer treatments.

Keywords: epigenetic modifications; gene transcription; histone modifications; metabolism; tumorigenesis

DOI: https://doi.org/10.3389/fcell.2021.654337