Methionine Commits Cells to Differentiate Into Plasmablasts Through Epigenetic Regulation of <scp>BTB</scp> and <scp>CNC</scp> Homolog 2 by the Methyltransferase <scp>EZH</scp>2

Zhang, Mingzeng; Iwata, S.; Hajime, Maiko; Ohkubo, Naoaki; Todoroki, Yasuyuki; Miyata, Hiroko; Ueno, Makoto; He, Hao; Zhang, Tong; Fan, Jie; Nakayamada, Shingo; Yamagata, Kazuya

doi:10.1002/art.41208

Cited by 29 publications

(40 citation statements)

References 51 publications

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“…EZH2 also promotes PC differentiation in activated human B cells. In these cells it has been shown to bind to the promoter of Bach2, a repressor of PC differentiation, and inhibit its expression via methylation ( 122 ). In contrast, chemical inhibition of EZH2 promoted murine PC differentiation in vitro , although antibody secretion was not enhanced ( 123 ).…”

Section: Altered Chromatin Accessibility In Sle B Cellsmentioning

confidence: 99%

Recent Advances in Lupus B Cell Biology: PI3K, IFNγ, and Chromatin

Bacalao

Satterthwaite

2021

Front. Immunol.

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In the autoimmune disease Systemic Lupus Erythematosus (SLE), autoantibodies are formed that promote inflammation and tissue damage. There has been significant interest in understanding the B cell derangements involved in SLE pathogenesis. The past few years have been particularly fruitful in three domains: the role of PI3K signaling in loss of B cell tolerance, the role of IFNγ signaling in the development of autoimmunity, and the characterization of changes in chromatin accessibility in SLE B cells. The PI3K pathway coordinates various downstream signaling molecules involved in B cell development and activation. It is governed by the phosphatases PTEN and SHIP-1. Murine models lacking either of these phosphatases in B cells develop autoimmune disease and exhibit defects in B cell tolerance. Limited studies of human SLE B cells demonstrate reduced expression of PTEN or increased signaling events downstream of PI3K in some patients. IFNγ has long been known to be elevated in both SLE patients and mouse models of lupus. New data suggests that IFNγR expression on B cells is required to develop autoreactive germinal centers (GC) and autoantibodies in murine lupus. Furthermore, IFNγ promotes increased transcription of BCL6, IL-6 and T-bet in B cells, which also promote GC and autoantibody formation. IFNγ also induces epigenetic changes in human B cells. SLE B cells demonstrate significant epigenetic reprogramming, including enhanced chromatin accessibility at transcription factor motifs involved in B cell activation and plasma cell (PC) differentiation as well as alterations in DNA methylation and histone modifications. Histone deacetylase inhibitors limit disease development in murine lupus models, at least in part via their ability to prevent B cell class switching and differentiation into plasma cells. This review will discuss relevant discoveries of the past several years pertaining to these areas of SLE B cell biology.

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Section: Altered Chromatin Accessibility In Sle B Cellsmentioning

confidence: 99%

Recent Advances in Lupus B Cell Biology: PI3K, IFNγ, and Chromatin

Bacalao

Satterthwaite

2021

Front. Immunol.

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“…18 Methionine metabolic regulation is crucial for the differentiation and function of CD4 T cells and B cells. [20][21][22] Restriction of methionine availability in activated T cells decreased the intracellular levels of SAM and histone methylation (active histone mark H3K4me3), impaired cell proliferation and cytokine production, and reduced the severity of experimental autoimmune encephalomyelitis (EAE) in mice. 21 In human B cells, extracellular methionine is required for BLIMP1-dependent plasmablast differentiation.…”

Section: One-carbon Metabolism and Sammentioning

confidence: 99%

“…21 In human B cells, extracellular methionine is required for BLIMP1-dependent plasmablast differentiation. 22 BACH2 represses the expression of PRDM1, which encodes BLIMP1. Methionine induced the H3K27 methyltransferase EZH2, which catalyzed the repressive mark H3K27me3 at the BACH2 locus and decreased the gene expression.…”

Section: One-carbon Metabolism and Sammentioning

confidence: 99%

“…Methionine induced the H3K27 methyltransferase EZH2, which catalyzed the repressive mark H3K27me3 at the BACH2 locus and decreased the gene expression. 22 Whether methionine affects SAM level was not addressed. In myeloid cells, Toll-like-receptor-4-stimulated macrophages require both exogenous serine and methionine to sustain the methionine cycle for generating SAM, which supports methylation reactions including the H3K36 trimethylation at the gene body of Il1b.…”

Section: One-carbon Metabolism and Sammentioning

confidence: 99%

“…Restriction of methionine availability in activated T cells decreased the intracellular levels of SAM and histone methylation (active histone mark H3K4me3), impaired cell proliferation and cytokine production, and reduced the severity of experimental autoimmune encephalomyelitis (EAE) in mice 21 . In human B cells, extracellular methionine is required for BLIMP1‐dependent plasmablast differentiation 22 . BACH2 represses the expression of PRDM1 , which encodes BLIMP1.…”

Section: One‐carbon Metabolism and Sammentioning

confidence: 99%

See 2 more Smart Citations

Circles of Life: linking metabolic and epigenetic cycles to immunity

Lio

Huang

2020

Immunology

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Metabolites are the essential substrates for epigenetic modification enzymes to write or erase the epigenetic blueprint in cells. Hence, the availability of nutrients and activity of metabolic pathways strongly influence the enzymatic function. Recent studies have shed light on the choreography between metabolome and epigenome in the control of immune cell differentiation and function, with a major focus on histone modifications. Yet, despite its importance in gene regulation, DNA methylation and its relationship with metabolism is relatively unclear. In this review, we will describe how the metabolic flux can influence epigenetic networks in innate and adaptive immune cells, with a focus on the DNA methylation cycle and the metabolites S-adenosylmethionine and a-ketoglutarate. Future directions will be discussed for this rapidly emerging field.

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Amelioration of Autoimmunity in a Lupus Mouse Model by Modulation of T‐Bet–Promoted Energy Metabolism in Pathogenic Age/Autoimmune‐Associated B Cells

Han

Hong

et al. 2023

Arthritis & Rheumatology

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Objective. Emerging evidence indicates that a distinct CD11c+T-bet+ B cell subset, termed age/autoimmuneassociated B cells (ABCs), is the major pathogenic autoantibody producer in lupus. Human lupus is associated with significant metabolic alterations, but how ABCs orchestrate their typical transcription factors and metabolic programs to meet specific functional requirements is unclear. We undertook this study to characterize the metabolism of ABCs and to identify the regulators of their metabolic pathways in an effort to develop new therapies for ABC-mediated autoimmunity.Methods. We developed a T-bet-tdTomato reporter mouse strain to trace live T-bet+ B cells and adoptively transferred CD4+ T cells from bm12 mice to induce lupus. We next sorted CD11c+tdTomato+ B cells and conducted RNA sequencing and an extracellular flux assay. A metabolic restriction to constrain ABC formation was tested in human and mouse B cells. We used a bm12-induced lupus mouse model to conduct the metabolic intervention.Results. ABCs exhibited a hypermetabolic state with enhanced glycolytic capacity. The increased glycolytic rate in ABCs was promoted by interferon-γ (IFNγ) signaling. T-bet, a downstream transcription factor of IFNγ, regulated the gene program of the glycolysis pathway in ABCs by repressing the expression of Bcl6. Functionally, glycolysis restriction could impair ABC formation. The engagement of glycolysis promoted survival and terminal differentiation of antibody-secreting cells. Administration of a glycolysis inhibitor ameliorated ABC accumulation and autoantibody production in the lupus-induced bm12 mouse model. Conclusion.T-bet can couple immune signals and metabolic programming to establish pathogenic ABC formation and functional capacities. Modulation of ABCs favored a metabolic program that could be a novel therapeutic approach for lupus.

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Methionine Commits Cells to Differentiate Into Plasmablasts Through Epigenetic Regulation of BTB and CNC Homolog 2 by the Methyltransferase EZH2

Cited by 29 publications

References 51 publications

Recent Advances in Lupus B Cell Biology: PI3K, IFNγ, and Chromatin

Recent Advances in Lupus B Cell Biology: PI3K, IFNγ, and Chromatin

Circles of Life: linking metabolic and epigenetic cycles to immunity

Amelioration of Autoimmunity in a Lupus Mouse Model by Modulation of T‐Bet–Promoted Energy Metabolism in Pathogenic Age/Autoimmune‐Associated B Cells

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