bims-meprid 2020-10-18 papers

Issue of 2020‒10‒18
five papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

Nat Metab. 2020 Oct 12.

Nuclear metabolism and the regulation of the epigenome.

Ruben Boon, Giorgia G Silveira, Raul Mostoslavsky.

Cellular metabolism has emerged as a major biological node governing cellular behaviour. Metabolic pathways fuel cellular energy needs, providing basic chemical molecules to sustain cellular homeostasis, proliferation and function. Changes in nutrient consumption or availability therefore can result in complete reprogramming of cellular metabolism towards stabilizing core metabolite pools, such as ATP, S-adenosyl methionine, acetyl-CoA, NAD/NADP and α-ketoglutarate. Because these metabolites underlie a variety of essential metabolic reactions, metabolism has evolved to operate in separate subcellular compartments through diversification of metabolic enzyme complexes, oscillating metabolic activity and physical separation of metabolite pools. Given that these same core metabolites are also consumed by chromatin modifiers in the establishment of epigenetic signatures, metabolite consumption on and release from chromatin directly influence cellular metabolism and gene expression. In this Review, we highlight recent studies describing the mechanisms determining nuclear metabolism and governing the redistribution of metabolites between the nuclear and non-nuclear compartments.

DOI: https://doi.org/10.1038/s42255-020-00285-4

Crit Rev Food Sci Nutr. 2020 Oct 12. 1-15

Dietary nutrients shape gut microbes and intestinal mucosa via epigenetic modifications.

Jianmin Wu, Ying Zhao, Xian Wang, Lingchang Kong, Lee J Johnston, Lin Lu, Xi Ma.

The imbalance of intestinal microecology firstly impairs intestinal mucosa barrier and function, then further damages the functions and homeostasis of distal organs, leading to systemic diseases. Nutrients, transplantation of bacteria flora and modes of life can shape gut microbiota and intestinal mucosa barrier and mitigate stress. Current researches demonstrate that dynamic epigenetic modifications of intestinal tissue strongly mediate the crosstalk between gut microbes and gut mucosa barrier. Lactobacillus and Bifidobacterium species can synthesize folate to increase DNA methylation and mRNA N6-methyladenosine (m6A) of gut, which ensures intestinal normal development. Clostridial cluster, Anaerostipes and Eubacterium can induce histone acylation modifications by butyrate to enhance the development and immune balance of gut. Herein, we summarizes the present scientific understanding of how dietary nutrients shape gut microbiota and further regulate intestinal mucosa functions via epigenetic modifications, which will shed light on manipulation of gut microbiota by dietary nutrients, for prevention or clinical treatment of intestinal diseases.

Keywords: Dietary nutrients; acetylation; crotonylation; epigenetic modification; gut microbiota; intestinal mucosa; methylation

DOI: https://doi.org/10.1080/10408398.2020.1828813

Free Radic Biol Med. 2020 Oct 12. pii: S0891-5849(20)31282-X. [Epub ahead of print]

miR-15a-5p inhibits metastasis and lipid metabolism by suppressing histone acetylation in lung cancer.

Yinyun Ni, Ying Yang, Jingjing Ran, Lu Zhang, Menglin Yao, Zhiqiang Liu, Li Zhang.

Metabolic reprogramme was a key characteristic of malignant tumors. Increased evidences indicated that besides Warburg effect (abnormal glucose metabolism), abnormal lipid metabolism played more and more important in progression and metastasis of malignant tumors. MiR-15a-5p could inhibit development of lung cancer, while its regulating mechanism, especially the role in lipid metabolism still remained unclear. In this study, we confirmed that miR-15a-5p inhibited proliferation, migration and invasion of lung cancer cells. The online analysis of Mirpath v.3 predicted that miR-15a-5p was closely associated with fatty acid synthesis and lipid metabolism. In vitro cell experiments revealed that miR-15a-5p significantly suppressed fatty acid synthesis of lung cancer cells by inhibiting acetate uptake. Extensive analysis indicated that miR-15a-5p could suppress acetyl-CoA activity and decrease histone H4 acetylation by inhibiting ACSS2 expression. In addition, we also observed that ACSS2 located in nucleus under hypoxic conditions, while miR-15a-5p could be transported into nucleus to inhibit the function of ACSS2. Our study unveiled a novel mechanism of miR-15a-5p in inhibiting metastasis of lung cancer cells by suppressing lipid metabolism via suppression of ACSS2 mediated acetyl-CoA activity and histone acetylation.

Keywords: ACSS2; acetylation; lipid metabolism; lung cancer; metastasis; miR-15a-5p

DOI: https://doi.org/10.1016/j.freeradbiomed.2020.10.009

Eur J Immunol. 2020 Oct 16.

Regulatory t cell metabolism at the intersection between autoimmune diseases and cancer.

Henry Kurniawan, Leticia Soriano-Baguet, Dirk Brenner.

Regulatory T cells (Tregs) are critical for peripheral immune tolerance and homeostasis, and altered Treg behavior is involved in many pathologies, including autoimmunity and cancer. The expression of the transcription factor FoxP3 in Tregs is fundamental to maintaining their stability and immunosuppressive function. Recent studies have highlighted the crucial role that metabolic reprogramming plays in controlling Treg plasticity, stability and function. In this review, we summarize how the availability and use of various nutrients and metabolites influence Treg metabolic pathways and activity. We also discuss how Treg-intrinsic metabolic programs define and shape their differentiation, FoxP3 expression, and suppressive capacity. Lastly, we explore how manipulating the regulation of Treg metabolism might be exploited in different disease settings to achieve novel immunotherapies. This article is protected by copyright. All rights reserved.

Keywords: Regulatory T cells; autoimmunity; cancer; metabolism

DOI: https://doi.org/10.1002/eji.201948470

Cell Biochem Biophys. 2020 Oct 11.

In Silico Prediction of Metabolic Fluxes in Cancer Cells with Altered S-adenosylmethionine Decarboxylase Activity.

Olga Dotsenko, Dmytro Shtofel.

This paper investigates the redistribution of metabolic fluxes in the cell with altered activity of S-adenosylmethionine decarboxylase (SAMdc, EC: 4.1.1.50), the key enzyme of the polyamine cycle and the common target for antitumor therapy. To address these goals, a stoichiometric metabolic model was developed that includes five metabolic pathways: polyamine, methionine, methionine salvage cycles, folic acid cycle, and the pathway of glutathione and taurine synthesis. The model is based on 51 reactions involving 57 metabolites, 31 of which are internal metabolites. All calculations were performed using the method of Flux Balance Analysis. The outcome indicates that the inactivation of SAMdc results in a significant increase in fluxes through the methionine, the taurine and glutathione synthesis, and the folate cycles. Therefore, when using therapeutic agents inactivating SAMdc, it is necessary to consider the possibility of cellular tumor metabolism reprogramming. S-adenosylmethionine affects serine methylation and activates serine-dependent de novo ATP synthesis. Methionine-depleted cell becomes methionine-dependent, searching for new sources of methionine. Inactivation of SAMdc enhances the transformation of S-adenosylmethionine to homocysteine and then to methionine. It also intensifies the transsulfuration process activating the synthesis of glutathione and taurine.

Keywords: Cancer cell; Flux balance analysis; Metabolic flux; Polyamine metabolism; S-adenosylmethionine decarboxylase; Stoichiometric model

DOI: https://doi.org/10.1007/s12013-020-00949-8