Dataset Information

Increased Expression of EZH2 Is Mediated by Higher Glycolysis and mTORC1 Activation in Lupus CD4+ T Cells.

ABSTRACT: Objective:EZH2 is overexpressed in CD4+ T cells from patients with systemic lupus erythematosus (SLE). Increased disease activity in SLE patients is associated with a proinflammatory epigenetic shift in naïve CD4+ T cells, likely mediated by EZH2. Here we aim to understand the upstream mechanisms underlying EZH2 overexpression in SLE CD4+ T cells. Methods:Naïve CD4+ T cells were isolated from SLE patients and then stimulated with anti-CD3/anti-CD28. qPCR and Western blotting were used to measure mRNA and protein expression levels, respectively. 2-Deoxy-d-glucose (2-DG) was used to inhibit glycolysis. mTORC1 signaling was inhibited using rapamycin. Oxidative stress was induced by H2O2. Results:Because glycolysis is increased in SLE CD4+ T cells and glycolysis regulates miR-26a and miR-101, which target EZH2, we examined the effect of inhibiting glycolysis on EZH2 expression. 2-DG significantly inhibited EZH2 expression in SLE CD4+ T cells. In addition, 2-DG restored the expression of miR-26a and miR-101, suggesting that suppression of EZH2 by 2-DG occurs at the post-transcriptional level. Because mTORC1 is activated in SLE CD4+ T cells in part due to increased oxidative stress, and mTORC1 activation increases glycolysis, we hypothesized that mTORC1 mediates increased EZH2 expression. Indeed, inhibiting mTORC1 increased miR-26a and miR-101 and suppressed EZH2 expression in SLE CD4+ T cells. Further, H2O2 treatment increased EZH2 expression, however, this effect appears to be independent of miR-26a and miR-101. Conclusion:Increased EZH2 is mediated by activation of mTORC1 and increased glycolysis in SLE CD4+ T cells. Therapeutic effects from inhibiting mTOR or glycolysis in SLE might be in part mediated by suppression of EZH2.

SUBMITTER: Zheng X

PROVIDER: S-EPMC7213603 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Increased Expression of EZH2 Is Mediated by Higher Glycolysis and mTORC1 Activation in Lupus CD4<sup>+</sup> T Cells.

Zheng Xiaoqing X Tsou Pei-Suen PS Sawalha Amr H AH

Immunometabolism 20200409 2

<h4>Objective</h4>EZH2 is overexpressed in CD4<sup>+</sup> T cells from patients with systemic lupus erythematosus (SLE). Increased disease activity in SLE patients is associated with a proinflammatory epigenetic shift in naïve CD4<sup>+</sup> T cells, likely mediated by EZH2. Here we aim to understand the upstream mechanisms underlying EZH2 overexpression in SLE CD4<sup>+</sup> T cells.<h4>Methods</h4>Naïve CD4<sup>+</sup> T cells were isolated from SLE patients and then stimulated with anti-CD ...[more]

PMID: 32395334

Similar Datasets

Project description:Histone methyltransferase enhancer of zeste homologue 2 (EZH2) forms an obligate repressive complex with suppressor of zeste 12 and embryonic ectoderm development, which is thought, along with EZH1, to be primarily responsible for mediating Polycomb-dependent gene silencing. Polycomb-mediated repression influences gene expression across the entire gamut of biological processes, including development, differentiation and cellular proliferation. Deregulation of EZH2 expression is implicated in numerous complex human diseases. To date, most EZH2-mediated function has been primarily ascribed to a single protein product of the EZH2 locus.We report that the EZH2 locus undergoes alternative splicing to yield at least two structurally and functionally distinct EZH2 methyltransferases. The longest protein encoded by this locus is the conventional enzyme, which we refer to as EZH2?, whereas EZH2?, characterized here, represents a novel isoform. We find that EZH2? localizes to the cell nucleus, complexes with embryonic ectoderm development and suppressor of zeste 12, trimethylates histone 3 at lysine 27, and mediates silencing of target promoters. At the cell biological level, we find that increased EZH2? induces cell proliferation, demonstrating that this protein is functional in the regulation of processes previously attributed to EZH2?. Biochemically, through the use of genome-wide expression profiling, we demonstrate that EZH2? governs a pattern of gene repression that is often ontologically redundant from that of EZH2?, but also divergent for a wide variety of specific target genes.Combined, these results demonstrate that an expanded repertoire of EZH2 writers can modulate histone code instruction during histone 3 lysine 27-mediated gene silencing. These data support the notion that the regulation of EZH2-mediated gene silencing is more complex than previously anticipated and should guide the design and interpretation of future studies aimed at understanding the biochemical and biological roles of this important family of epigenomic regulators.

Dataset Information

Increased Expression of EZH2 Is Mediated by Higher Glycolysis and mTORC1 Activation in Lupus CD4+ T Cells.

Publications

Increased Expression of EZH2 Is Mediated by Higher Glycolysis and mTORC1 Activation in Lupus CD4<sup>+</sup> T Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets