Transcriptional regulator Bhlhe40 works as a cofactor of T-bet in the regulation of IFN-γ production in<i>i</i>NKT cells

Kanda, Masatoshi; Yamanaka, Hidetoshi; Kojo, Satoshi; Usui, Yuu; Honda, Hiroaki; Sotomaru, Yusuke; Harada, Michishige; Taniguchi, Masaru; Suzuki, Nao; Atsumi, Tatsuya; Wada, Haruka; Baghdadi, Muhammad; Seino, K.

doi:10.1073/pnas.1604178113

Cited by 46 publications

(50 citation statements)

References 52 publications

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“…To determine the transcription factors that bind these super-enhancers, we performed motif analysis and found enrichment of the transcription factors RelA and Bhlhe40 (Supplementary Fig. 8e), which were recently shown to cooperate with T-bet to control i NKT cell functions 42 . Although a small fraction of super-enhancers ( n = 13) gained accessibility in UTX-KO i NKT cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

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The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells

et al. 2016

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Invariant natural killer T (iNKT) cells are innate-like lymphocytes that protect against infection, autoimmune disease and cancer. However, little is known about epigenetic regulation of iNKT cell development. Here, we show that the H3K27me3 histone demethylase UTX is an essential cell-intrinsic factor that controls an iNKT lineage-specific gene expression program and epigenetic landscape in a demethylase activity dependent manner. UTX-deficient iNKT cells exhibited impaired expression of iNKT signature genes due to a decrease in activation-associated H3K4me3 and an increase in repressive H3K27me3 marks within the promoters that UTX occupies. We identified JunB as a novel regulator of iNKT development and show that target gene expression of both JunB and iNKT master transcription factor PLZF was UTX-dependent. We determined iNKT super-enhancers and demonstrated that UTX-mediated regulation of super-enhancer accessibility was a key mechanism for iNKT lineage commitment. These findings reveal how UTX regulates iNKT cell development through multiple epigenetic mechanisms.

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Section: Resultsmentioning

confidence: 99%

“…ATAC-Seq was performed as previously described 42 . Briefly, WT and UTX-KO thymic i NKT cells were sorted by FACS and lysed in lysis buffer containing 10 mM Tris-HCl pH 7.4, 10 mM NaCl, 3 mM MgCl 2 , 0.1% IGEPAL CA-360.…”

Section: Methodsmentioning

confidence: 99%

The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells

et al. 2016

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“…REST (REI-silencing transcription factor) inactivation has been shown using a transgenic approach to induce de novo methylation and conversely, the expression of REST was sufficient to restore the unmethylated state of the DNA sequence bound [52]. Direct association between HDAC2 (Histone deacetylase 2), EWSR1 (Ewing sarcoma breakpoint region1), FLI1, SP4/1 and BHLHE40 (Basic helixloop-helix family member E40) and changes in DNA methylation have not yet been demonstrated but they have been previously associated with changes in histone methylation or acetylation [53][54][55][56][57]. Numerous evidence supports a complex interplay between histone modification and DNA methylation (for review [58,59]).…”

Section: Transcription Factor Binding Sites Enrichment Analysismentioning

confidence: 99%

Genetic variants influence on the placenta regulatory landscape

Delahaye

Kong

et al. 2018

Preprint

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Background: From genomic association studies, quantitative trait loci analysis, and epigenomic mapping, it is evident that significant efforts are necessary to define geneticepigenetic interactions and understand their role in disease susceptibility and progression. For this reason, an analysis of the effects of genetic variation on gene expression and DNA methylation in human placentas at high resolution and wholegenome coverage will have multiple mechanistic and practical implications.Results: By producing and analyzing DNA sequence variation (n=303), DNA methylation (n=303) and mRNA expression data (n=80) from placentas from healthy women, we investigate the regulatory landscape of the human placenta and offer analytical approaches to integrate different types of genomic data and address some potential limitations of current platforms. We distinguish two profiles of interaction between expression and DNA methylation, revealing linear or bimodal effects, reflecting differences in genomic context, transcription factor recruitment, and possibly cell subpopulations.Conclusions: These findings help to clarify the interactions of genetic, epigenetic, and transcriptional regulatory mechanisms in normal human placentas. They also provide strong evidence for genotype-driven modifications of transcription and DNA methylation in normal placentas. In addition to these mechanistic implications, the data and analytical methods presented here will improve the interpretability of genome-wide and epigenome-wide association studies for human traits and diseases that involve placental functions. Author summaryThe placenta is a critical organ playing multiple roles including oxygen and metabolite transfer from mother to fetus, hormone production, and vascular perfusion. With this study, we aimed to deliver a placenta-specific regulatory map based on a combination of publicly available and newly generated data. To complete this reference, we obtained genotype information (n=303), DNA methylation (n=303) and expression data (n=80) for placentas from healthy women. Our analysis of methylation and expression quantitative trait loci (QTLs) and correlations between methylation and expression data were designed to identify fundamental associations between genome, transcriptome, and epigenome in this key fetal organ. The results provide high-resolution genetic and epigenetic maps specific to the placenta based on a representative ethnically diverse cohort. As interest and efforts are growing to better understand the etiology of placental disease and the impact of the environment on placental function these data will provide a reference and enhance future investigations.

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“…4 It has been reported that BHLHE40 is upregulated in GC tissues and required for anti-apoptotic activity of GC cells under hypoxia. BHLHE40 is an important regulatory factor in the cell proliferation and apoptosis, as well as immune responses and circadian rhythms.…”

Section: Introductionmentioning

confidence: 99%

“…BHLHE40 is an important regulatory factor in the cell proliferation and apoptosis, as well as immune responses and circadian rhythms. 4 It has been reported that BHLHE40 is upregulated in GC tissues and required for anti-apoptotic activity of GC cells under hypoxia. 5,6 As H pylori is one of the strongest risk factors for GC and has been well-established to participate in the development and progression of GC, 7 it is therefore interesting to explore whether BHLHE40 is regulated during H pylori infection and which gene programs BHLHE40 controls.…”

Section: Introductionmentioning

confidence: 99%

Upexpression of BHLHE40 in gastric epithelial cells increases CXCL12 production through interaction with p‐STAT3 in Helicobacter pylori‐associated gastritis

Teng

Zhao

et al. 2019

The FASEB Journal

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BHLHE40, a member of the basic helix-loop-helix transcription factor family, has been reported to play an important role in inflammatory diseases. However, the regulation and function of BHLHE40 in Helicobacter pylori (H pylori)-associated gastritis is unknown. We observed that gastric BHLHE40 was significantly elevated in patients and mice with H pylori infection. Then, we demonstrate that H pyloriinfected GECs express BHLHE40 via cagA-ERK pathway. BHLHE40 translocates to cell nucleus, and then binds to cagA protein-activated p-STAT3 (Tyr705). The complex increases chemotactic factor CXCL12 expression (production). Release of CXCL12 from GECs fosters CD4 + T cell infiltration in the gastric mucosa. Our results identify the cagA-BHLHE40-CXCL12 axis that contributes to inflammatory response in gastric mucosa during H pylori infection.

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

Cited by 46 publications

References 52 publications

The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells

The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells

Genetic variants influence on the placenta regulatory landscape

Upexpression of BHLHE40 in gastric epithelial cells increases CXCL12 production through interaction with p‐STAT3 in Helicobacter pylori‐associated gastritis

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