Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity

Tanaka, Shinya; Ise, Wataru; Inoue, Takeshi; Ito, Ayako; Ono, Chisato; Shima, Yoshihito; Sakakibara, Shuhei; Nakayama, Manabu; Fujii, Kentaro; Miura, Ikuo; Sharif, Jafar; Koseki, Haruhiko; Koni, Pandelakis A.; Raman, Indu; Li, Quan Zhen; Kubo, Masato; Fujiki, Katsunori; Nakato, Ryuichiro; Shirahige, Katsuhiko; Araki, Hiromitsu; Miura, Fumihito; Ito, Takashi; Kawakami, Eiryo; Baba, Yoshifumi; Kurosaki, Tomohiro

doi:10.1038/s41590-020-0700-y

Cited by 70 publications

(59 citation statements)

References 57 publications

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“…TET2 has been shown to recruit histone deacetylases (HDAC1/2) to specific gene loci, thereby mediating the transcriptional repression in immune cells [ 34 , 35 ]. Therefore, we performed ChIP-qPCR analysis of HDAC1 and HDAC2 in WT and TET2 KO MCF7 cells.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to the well-known DNA demethylation activity, TET proteins have been shown to recruit histone deacetylases (HDACs) and mediate transcriptional repression in immune cells [ 34 , 35 , 36 ]. Coincidentally, our study demonstrates that TET2 recruits HDAC1/2 to deacetylate H3K27ac at PD-L1 promoter and results in the transcriptional suppression of PD-L1 gene.…”

Section: Discussionmentioning

confidence: 99%

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TET2 Inhibits PD-L1 Gene Expression in Breast Cancer Cells through Histone Deacetylation

Shen

Liu

Wang

et al. 2021

Cancers

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Activation of PD-1/PD-L1 checkpoint is a critical step for the immune evasion of malignant tumors including breast cancer. However, the epigenetic mechanism underlying the aberrant expression of PD-L1 in breast cancer cells remains poorly understood. To investigate the role of TET2 in the regulation of PD-L1 gene expression, quantitative reverse transcription PCR (RT-qPCR), Western blotting, chromatin immunoprecipitation (ChIP) assay and MeDIP/hMeDIP-qPCR were performed on MCF7 and MDA-MB-231 human breast cancer cells. Here, we reported that TET2 depletion upregulated PD-L1 gene expression in MCF7 cells. Conversely, ectopic expression of TET2 inhibited PD-L1 gene expression in MDA-MB-231 cells. Mechanistically, TET2 protein recruits histone deacetylases (HDACs) to PD-L1 gene promoter and orchestrates a repressive chromatin structure to suppress PD-L1 gene transcription, which is likely independent of DNA demethylation. Consistently, treatment with HDAC inhibitors upregulated PD-L1 gene expression in wild-type (WT) but not TET2 KO MCF7 cells. Furthermore, analysis of the CCLE and TCGA data showed a negative correlation between TET2 and PD-L1 expression in breast cancer. Taken together, our results identify a new epigenetic regulatory mechanism of PD-L1 gene transcription, linking the catalytic activity-independent role of TET2 to the anti-tumor immunity in breast cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TET2 Inhibits PD-L1 Gene Expression in Breast Cancer Cells through Histone Deacetylation

Shen

Liu

Wang

et al. 2021

Cancers

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“…In this regard, vitamin C accumulates within hematopoietic stem cells (HSC) to promote Tet activity, thereby suppressing leukemogenesis [64]. As Tet enzymes play an important role in maintaining the homeostasis of immunity [65][66][67], activation of Tet by vitamin C might counteract dysregulated immune responses seen in inflammatory disorders, such as sepsis. The interaction between vitamin C and Tet enzymes as well as stem cell homeostasis in the context of inflammatory syndrome and sepsis warrants investigations.…”

Section: As An Important Player In Stem Cell Biology and Epigeneticsmentioning

confidence: 99%

Vitamin C for sepsis intervention: from redox biochemistry to clinical medicine

Zhu

2021

Mol Cell Biochem

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Vitamin C, also known as ascorbic acid or ascorbate, is a water-soluble vitamin synthesized in plants as well as in animals except humans and several other animal species. Humans obtain vitamin C from dietary sources and via vitamin supplementation. Vitamin C possesses important biological functions, including serving as a cofactor for many enzymes, acting as an antioxidant and anti-inflammatory compound, and participating in regulating stem cell biology and epigenetics. The multifunctional nature of vitamin C contributes to its essentialness in maintaining and safeguarding physiological homeostasis, especially regulation of immunity and inflammatory responses. In this context, vitamin C has been investigated for its efficacy in treating diverse inflammatory disorders, including sepsis, one of the major causes of death globally and for which currently there is no cure. Accordingly, this Mini-Review surveys recent major research findings on the effectiveness of vitamin C and the underling molecular mechanisms in sepsis intervention in both experimental animal models and randomized controlled trials. To set a stage for discussing the effects and mechanisms of vitamin C in sepsis intervention, this Mini-Review begins with an overview of vitamin C redox biochemistry and its multifunctional properties.

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“…Tet2 and Tet3 can both demethylate DNA and recruit HDACs ( 116 ). B cell specific deletion of both Tet2 and Tet3 results in increased activation of B and T cells, autoantibody production, and a mild autoimmune disease ( 117 ). This depends on B/T interactions and results from enhanced expression of the costimulatory molecule CD86 on B cells.…”

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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Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity

Cited by 70 publications

References 57 publications

TET2 Inhibits PD-L1 Gene Expression in Breast Cancer Cells through Histone Deacetylation

TET2 Inhibits PD-L1 Gene Expression in Breast Cancer Cells through Histone Deacetylation

Vitamin C for sepsis intervention: from redox biochemistry to clinical medicine

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

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