The Role of the Basic Helix-Loop-Helix Transcription Factor<i>Dec1</i>in the Regulatory T Cells

Miyazaki, Kazuko; Miyazaki, Masaki; Guo, Yun; Yamasaki, Norimasa; Kanno, Morio; Honda, Zen Ichiro; Oda, Hideaki; Kawamoto, Hiroshi; Honda, Hiroaki

doi:10.4049/jimmunol.1001381

Cited by 48 publications

(66 citation statements)

References 52 publications

(44 reference statements)

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“…Bhlhe40 is a transcriptional regulator expressed in a wide range of cells and is involved in various physiological functions, including cellular growth and proliferation, immune responses, and circadian rhythm (11,13). As part of the Immunological Genome Project indicated, Bhlhe40 shows high expression levels in iNKT cells (35); however, the function of Bhlhe40 remained unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Lenti-X 293T, B16, and EL-4 cells were purchased from Clontech Laboratory, ATCC, and RIKEN Cell Bank, respectively, and were cultured in appropriate medium supplemented with 10% (vol/vol) FBS in a 5% CO 2 incubator at 37°C. C57BL/6 mice were purchased from Japan SLC, Inc. Bhlhe40 −/− mice and Jα18 −/− mice were generated as previously reported (11,46). NKT clone mice were generated from NKT-NT-ES cells by nuclear transfer of iNKT cells (47), whereas Bhlhe40 −/− NKT clone mice were generated by crossing Bhlhe40 were stained with α-IFN-γ or α-IL-4 Abs.…”

Section: Methodsmentioning

confidence: 99%

“…cgi)] for the screening of candidate genes that might be involved in the regulation of IFN-γ production in iNKT cells and identified basic-helix-loop-helix family, member e40 (Bhlhe40) as a key regulator of iNKT cell-derived IFN-γ. Bhlhe40 belongs to the basic helix-loop-helix protein family and acts as a regulating transcription factor that controls a wide variety of biological processes, including cellular growth, proliferation, apoptosis, immune responses, and the regulation of circadian rhythms (10)(11)(12)(13).…”

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confidence: 99%

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Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production iniNKT cells

Kanda

Yamanaka

Kojo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Invariant natural killer T (iNKT) cells are a subset of innate-like T cells that act as important mediators of immune responses. In particular, iNKT cells have the ability to immediately produce large amounts of IFN-γ upon activation and thus initiate immune responses in various pathological conditions. However, molecular mechanisms that control IFN-γ production in iNKT cells are not fully understood. Here, we report that basic helix-loop-helix transcription factor family, member e40 (Bhlhe40), is an important regulator for IFN-γ production in iNKT cells. Bhlhe40 is highly expressed in stage 3 thymic iNKT cells and iNKT1 subsets, and the level of Bhlhe40 mRNA expression is correlated with Ifng mRNA expression in the resting state. Although Bhlhe40-deficient mice show normal iNKT cell development, Bhlhe40-deficient iNKT cells show significant impairment of IFN-γ production and antitumor effects. Bhlhe40 alone shows no significant effects on Ifng promoter activities but contributes to enhance T-box transcription factor Tbx21 (T-bet)-mediated Ifng promoter activation. Chromatin immunoprecipitation analysis revealed that Bhlhe40 accumulates in the T-box region of the Ifng locus and contributes to histone H3-lysine 9 acetylation of the Ifng locus, which is impaired without T-bet conditions. These results indicate that Bhlhe40 works as a cofactor of T-bet for enhancing IFN-γ production in iNKT cells.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production iniNKT cells

Kanda

Yamanaka

Kojo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Members of this family are known to respond to environmental stimuli and regulate several physiological processes in diverse cell types, including the cell cycle, apoptosis, and differentiation via their actions as both transcriptional activators and repressors. Bhlhe40 is expressed in T cells upon T cell receptor (TCR) stimulation 38 . Bhlhe40 −/− mice develop a non-fully penetrant late-onset (age greater than ~8 months) lymphoproliferative disease associated with autoantibodies 38,39 , that may be due to a requirement for Bhlhe40 for Treg maintenance during aging.…”

Section: Introductionmentioning

confidence: 99%

Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation

et al. 2014

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TH1 and TH17 cells mediate neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Pathogenic TH cells in EAE must produce the pro-inflammatory cytokine granulocyte-macrophage colony stimulating factor (GM-CSF). TH cell pathogenicity in EAE is also regulated by cell-intrinsic production of the immunosuppressive cytokine interleukin 10 (IL-10). Here, we demonstrate that mice deficient for the basic helix-loop-helix (bHLH) transcription factor Bhlhe40 (Bhlhe40−/−) are resistant to the induction of EAE. Bhlhe40 is required in vivo in a T cell-intrinsic manner, where it positively regulates the production of GM-CSF and negatively regulates the production of IL-10. In vitro, GM-CSF secretion is selectively abrogated in polarized Bhlhe40−/− TH1 and TH17 cells, and these cells show increased production of IL-10. Blockade of IL-10 receptor in Bhlhe40−/− mice renders them susceptible to EAE. These findings identify Bhlhe40 as a critical regulator of autoreactive T cell pathogenicity.

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“…51 Additional roles of BHLHE40 and other differentially methylated transcription factors can be found in Table 3. 13,[52][53][54][55][56][57] Based on its role in T and NKT development and apparent significance in NK cell activation, several ddPCR assays for quantitating BHLHE40 demethylation were designed and evaluated. Cloning and bisulfite sequencing revealed broad and heterogeneous demethylation within the exon 5 region.…”

Section: Transcription Factors: Bhlhe40 Zbtb32/fazf Nfatc1 Bach2mentioning

confidence: 99%

The DNA methylation profile of activated human natural killer cells

et al. 2016

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Natural killer (NK) cells are now recognized to exhibit characteristics akin to cells of the adaptive immune system. The generation of adaptive memory is linked to epigenetic reprogramming including alterations in DNA methylation. The study herein found reproducible genome wide DNA methylation changes associated with human NK cell activation. Activation led predominately to CpG hypomethylation (81% of significant loci). Bioinformatics analysis confirmed that non-coding and gene-associated differentially methylated sites (DMS) are enriched for immune related functions (i.e., immune cell activation). Known DNA methylation-regulated immune loci were also identified in activated NK cells (e.g., TNFA, LTA, IL13, CSF2). Twenty-one loci were designated high priority and further investigated as potential markers of NK activation. BHLHE40 was identified as a viable candidate for which a droplet digital PCR assay for demethylation was developed. The assay revealed high demethylation in activated NK cells and low demethylation in na€ ıve NK, T-and B-cells. We conclude the NK cell methylome is plastic with potential for remodeling. The differentially methylated region signature of activated NKs revealed similarities with T cell activation, but also provided unique biomarker candidates of NK activation, which could be useful in epigenome-wide association studies to interrogate the role of NK subtypes in global methylation changes associated with exposures and/or disease states.

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The Role of the Basic Helix-Loop-Helix Transcription FactorDec1in the Regulatory T Cells

Abstract: Material

Cited by 48 publications

References 52 publications

Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production iniNKT cells

Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production iniNKT cells

Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation

The DNA methylation profile of activated human natural killer cells

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