Active Transcription of the Human FASL/CD95L/TNFSF6 Promoter Region in T Lymphocytes Involves Chromatin Remodeling

Castellano, Rémy; Vire, Bérengère; Pion, Marjorie; Quivy, Vincent; Olive, Daniel; Hirsch, Ivan; Lint, Carine Van; Collette, Yves

doi:10.1074/jbc.m602373200

Cited by 16 publications

(12 citation statements)

References 80 publications

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“…Importantly, these data show that coordinated H3K4/H3K9 methylation/demethylation plays a significant role in the regulation of activation-induced FasL gene expression under normal as well as pathologic conditions. Similar co-ordinated modulation of H3K4 and H3K9 methylation has also been observed as a regulatory feature of other actively transcribed genes (22, 23, 28, 50–52). …”

Section: Discussionsupporting

confidence: 67%

“…Earlier work, based on DNAse hypersensitivity of the FasL 5′-regulatory region indicated that chromatin remodeling is a primary event in the transcriptional activation of FasL gene expression (28). To further elucidate the epigenetic mechanisms underlying FasL promoter chromatin remodeling and transcriptional activation, we examined the TCR-stimulation responsive histone modifications in primary human CD4+ T lymphocytes under normal and the pathologic conditions of alcohol exposure.…”

Section: Introductionmentioning

confidence: 99%

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Coordinated Histone H3 Methylation and Acetylation Regulate Physiologic and Pathologic Fas Ligand Gene Expression in Human CD4+ T Cells

Ghare

Joshi‐Barve

Moghe

et al. 2014

The Journal of Immunology

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Activation-induced Fas Ligand (FasL) mRNA expression in CD4+ T cells is mainly controlled at transcriptional initiation. To elucidate the epigenetic mechanisms regulating physiologic and pathologic FasL transcription, TCR-stimulation responsive promoter histone modifications in normal and alcohol-exposed primary human CD4+ T cells were examined. TCR stimulation of normal and alcohol-exposed cells led to discernible changes in promoter histone H3 lysine trimethylation, documented by an increase in the levels of transcriptionally permissive H3K4Me3 and a concomitant decrease in the repressive H3K9Me3. Moreover, acetylation of H3K9 (H3K9Ac), a critical feature of the active promoter state which is opposed by H3K9Me3, was significantly increased and was essentially mediated by the p300-histone acetyltransferase (p300-HAT). Notably, the degree of these coordinated histone modifications and subsequent recruitment of transcription factors and RNA polymerase II (RNA Pol II) was significantly enhanced in alcohol exposed CD4+ T cells and was commensurate with the pathologic increase in the levels of FasL mRNA. The clinical relevance of these findings is further supported by CD4+ T cells obtained from individuals with a history of heavy alcohol consumption that demonstrate significantly greater p300-dependent H3K9 acetylation and FasL expression. Overall, these data show that in human CD4+ T cells, TCR stimulation induces a distinct promoter histone profile involving a coordinated crosstalk between H3K4 and H3K9 methylation and acetylation that dictates the transcriptional activation of FasL under physiologic as well as pathologic conditions of alcohol exposure.

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Coordinated Histone H3 Methylation and Acetylation Regulate Physiologic and Pathologic Fas Ligand Gene Expression in Human CD4+ T Cells

Ghare

Joshi‐Barve

Moghe

et al. 2014

The Journal of Immunology

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“…Nuclei were purified and submitted to nuclease digestion as previously described [21]. Briefly, cells were lysed at 4°C in 0.2% NP40 buffer followed by nuclease digestion using DNase I (10 min at 4°C).…”

Section: Methodsmentioning

confidence: 99%

Anti-Leukemia Activity of MS-275 Histone Deacetylase Inhibitor Implicates 4-1BBL/4-1BB Immunomodulatory Functions

et al. 2009

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Histone deacetylase inhibitors (HDACi) have demonstrated promising therapeutic potential in clinical trials for hematological malignancies. HDACi, such as SAHA/Vorinostat, Trichostatin A, and MS-275 were found to induce apoptosis of leukemic blasts through activation of the death receptor pathway and transcriptional induction of the Tumor Necrosis Factor (TNF)-related pro-apoptotic family members, TRAIL and FasL. The impact of HDACi on TNF-related costimulatory molecules such as 4-1BB ligand (4-1BBL/TNFSF9) is however not known. Following exposure to SAHA/Vorinostat, Trichostatin A, and MS-275, transcript levels were determined by real time PCR in Jurkat, Raji and U937 cells. Treatment with HDACi up-regulated TNFSF9 gene expression in the three leukemia cell lines, yet to different extend and with distinct kinetics, which did not require de novo protein synthesis and was not associated with DNAse I hypersensitive chromatin remodeling. Transcriptional activity of TNFSF9 promoter-luciferase constructs was induced up to 12 fold by HDACi, and implication of Sp1/Sp3 transcription factors binding to functional GC-box elements was evidenced by reporter gene assays, site-directed mutagenesis, and electrophoretic mobility shift assays. Functionality of modulated target genes was assessed in allogeneic mixed leukocyte reaction experiments. MS-275- and to a lesser extent Trichostatin A- and SAHA-treated Raji cells significantly up regulated T lymphocytes proliferation which was reduced by about 50% by a 4-1BB blocking recombinant protein, while MS-275- but neither Trichostatin A- nor SAHA-treated cells up-regulated IFNγ secretion by T lymphocytes. Our results identify 4-1BBL/4-1BB as a downstream target of HDACi, especially of MS-275 anti-leukemia action in vitro. Thus, HDACi such as MS-275 displaying dual TNF-dependent proapoptotic and costimulatory activities might be favored for inclusion in HDACi-based anti-cancer therapeutic strategies.

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“…However, the role of FasL expression and apoptotic death in AZT induced hepatotoxicity has not been examined. We and others have shown that promoter-associated epigenetic modifications are known to regulate FasL gene expression (Castellano et al, 2006; Ghare et al, 2014; Holtz-Heppelmann et al, 1998; Li-Weber and Krammer, 2003). Hence, the present study examines the potential hepatotoxic interactions between acrolein and the ART drug, AZT.…”

Section: Introductionmentioning

confidence: 99%

Acrolein enhances epigenetic modifications, FasL expression and hepatocyte toxicity induced by anti-HIV drug Zidovudine

Ghare

Donde

Chen

et al. 2016

Toxicology in Vitro

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Zidovudine (AZT) remains the mainstay of antiretroviral therapy against HIV in resource-poor countries; however, its use is frequently associated with hepatotoxicity. Not all HIV patients on AZT develop hepatotoxicity, and the determining factors are unclear. Alcohol consumption and cigarette smoking are known risk factors for HIV hepatotoxicity, and both are significant sources of acrolein, a highly reactive and toxic aldehyde. This study examines the potential hepatotoxic interactions between acrolein and AZT. Our data demonstrate that acrolein markedly enhanced AZT-induced transcriptionally permissive histone modifications (H3K9Ac and H3K9Me3) allowing the recruitment of transcription factor NF-kB and RNA polymerase II at the FasL gene promoter, resulting in FasL upregulation and apoptosis in hepatocytes. Notably, the acrolein scavenger, hydralazine prevented these promoter-associated epigenetic changes and inhibited FasL upregulation and apoptosis induced by the combination of AZT and acrolein, as well as AZT alone. Our data strongly suggest that acrolein enhancement of promoter histone modifications and FasL upregulation are major pathogenic mechanisms driving AZT-induced hepatotoxicity. Moreover, these data also indicate the therapeutic potential of hydralazine in mitigating AZT hepatotoxicity.

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Active Transcription of the Human FASL/CD95L/TNFSF6 Promoter Region in T Lymphocytes Involves Chromatin Remodeling

Cited by 16 publications

References 80 publications

Coordinated Histone H3 Methylation and Acetylation Regulate Physiologic and Pathologic Fas Ligand Gene Expression in Human CD4+ T Cells

Coordinated Histone H3 Methylation and Acetylation Regulate Physiologic and Pathologic Fas Ligand Gene Expression in Human CD4+ T Cells

Anti-Leukemia Activity of MS-275 Histone Deacetylase Inhibitor Implicates 4-1BBL/4-1BB Immunomodulatory Functions

Acrolein enhances epigenetic modifications, FasL expression and hepatocyte toxicity induced by anti-HIV drug Zidovudine

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