Histone hyperacetylated domains across the
            <i>Ifng</i>
            gene region in natural killer cells and T cells

Chang, Shaojing; Aune, Thomas M.

doi:10.1073/pnas.0502129102

Cited by 79 publications

(106 citation statements)

References 37 publications

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“…Epigenetic regulation of IFN-␥ gene expression differs between NK and T cells. NK cells are poised to rapidly transcribe IFN-␥ as this locus is constitutively and extensively hyperacetylated and hypomethylated, increasing chromatin accessibility for binding of both positive and negative transcriptional regulators (10)(11)(12). In contrast, histone acetylation at the IFN-␥ locus in T cells depends on activation by Th1-skewing factors (such as IL-12) and proliferation (10,11,29).…”

Section: Discussionmentioning

confidence: 99%

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ATF3 regulates MCMV infection in mice by modulating IFN-γ expression in natural killer cells

Rosenberger

Clark

Treuting

et al. 2008

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

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Activating transcription factor 3 (ATF3) is a negative regulator of proinflammatory cytokine expression in macrophages, and ATF3-deficient mice are more susceptible to endotoxic shock. Here, we demonstrate that ATF3 interacts with a cis-regulatory element of the IFN-␥ gene in natural killer (NK) cells, and that ATF3null NK cells show increased transcription and secretion of IFN-␥. NK cellderived IFN-␥ has previously been demonstrated to be protective against murine cytomegalovirus (MCMV) infection, and we show here that ATF3null mice exhibit decreased hepatic viral load and reduced liver histopathology upon challenge with MCMV. Reconstitution of NK-deficient mice with ATF3null NK cells more effectively controlled MCMV infection than mice reconstituted with WT cells, indicating that ATF3 acts within NK cells to regulate antiviral responses.cytomegalovirus ͉ infectious disease ͉ transcription factor ͉ viral immunity I nterferon (IFN)-␥ is a pleiotropic cytokine that functions at the innate-adaptive immune interface to promote antibacterial, antitumor, and antiviral responses (1). IFN-␥ is produced by natural killer (NK), NKT, CD4 ϩ , and/or CD8 ϩ T cells stimulated with the T helper (Th1)-skewing cytokines IL-12 and/or IL-18, with the cellular source of IFN-␥ depending on the specific disease model. Murine cytomegalovirus (MCMV) is a herpes virus that causes a systemic infection, and NK cell production of IFN-␥ early during infection is absolutely required for antiviral control (2). IFN-␥ has many effects during MCMV infection; in general, it modulates the host response by regulating the production of cytokines and chemokines to recruit and activate effector cells (3), increasing the levels of MHC class I (4), and activating antiviral effector mechanisms (5, 6). A similar role for IFN-␥ and NK cells in regulating herpes virus infection in humans has been suggested by genetic deficiency studies (ref. 7 and reviewed in refs. 8 and 9).Although much is known about the regulation of IFN-␥ expression in T cells, less is understood about this process in NK cells. It is known that the transcription factors and epigenetic modifications that regulate expression at the IFN-␥ locus are different in T cells and NK cells (10-12). The transcription factors SMAD3 (13), NF-Bp50 (14), Hlx (15), and Runx3 (16) negatively regulate IFN-␥ transcription in NK cells. Tight regulation of IFN-␥ expression is required to limit pathology; however, the impact of negative regulators of IFN-␥ expression in NK cells on disease has not been explored.Our laboratory previously identified activating transcription factor 3 (ATF3) as an important negative regulator of proinflammatory cytokine gene expression in macrophages by using transcriptional profiling and computational analysis (17). Here, we observe that ATF3 expression is highly induced in the livers of MCMV-infected mice and purified NK cells. Results ATF3null Mice Show Enhanced Protection Against MCMV Infection.The mouse liver is a major target organ for MCMV replication. We observed that ...

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Section: Discussionmentioning

confidence: 99%

“…It is known that the transcription factors and epigenetic modifications that regulate expression at the IFN-␥ locus are different in T cells and NK cells (10)(11)(12). The transcription factors SMAD3 (13), NF-Bp50 (14), Hlx (15), and Runx3 (16) negatively regulate IFN-␥ transcription in NK cells.…”

mentioning

confidence: 99%

ATF3 regulates MCMV infection in mice by modulating IFN-γ expression in natural killer cells

Rosenberger

Clark

Treuting

et al. 2008

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

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“…Stimulation of NK cells with IL-12 and IL-18 leads to production of IFN-γ as well as elevation of cytotoxic activity (8,9). It has been shown that sequence elements conserved among species (also known as conserved noncoding sequences, CNSs) present up to 100 kb from the transcription start site (TSS) of Ifng are involved in controlling the expression of IFN-γ (7,(10)(11)(12). Various transcription factors are recruited to the CNS of Ifng.…”

Section: Ifn-γ | Transcription | Virus Infection | Stat4mentioning

confidence: 99%

“…It has been shown that histones of the Ifng loci were hyperacetylated even in the absence of stimulation in NK cells, compared with T cells (10). We performed ChIP analysis with anti-acetyl histone 3 lysine 9 (H3K9) antibody to assess H3K9 acetylation in Ifng CNS.…”

Section: Iκbζ Is Required For Change In Histone 3 Lysine 9 Acetylatiomentioning

confidence: 99%

IκBζ is essential for natural killer cell activation in response to IL-12 and IL-18

Miyake

Satoh

Kato

et al. 2010

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

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IκBζ, encoded by Nfibiz , is a nuclear IκB-like protein harboring ankyrin repeats. IκBζ has been shown to regulate IL-6 production in macrophages and Th17 development in T cells. However, the role of IκBζ in natural killer (NK) cells has not be understood. In the present study, we found that the expression of IκBζ was rapidly induced in response to IL-18 in NK cells, but not in T cells. Analysis of Nfkbiz −/− mice revealed that IκBζ was essential for the production of IFN-γ production and cytotoxic activity in NK cells in response to IL-12 and/or IL-18 stimulation. IL-12/IL-18–mediated gene induction was profoundly impaired in Nfkbiz −/− NK cells. Whereas the phosphorylation of STAT4 was normally induced by IL-12 stimulation, STAT4 was not recruited to the Ifng gene regions in Nfkbiz −/− NK cells. Acetylation of histone 3 K9 on Ifng regions was also abrogated in Nfkbiz −/− NK cells. IκBζ was recruited on the proximal promoter region of the Ifng gene, and overexpression of IκBζ together with IL-12 activated the Ifng promoter. Furthermore, Nfkbiz −/− mice were highly susceptible to mouse MCMV infection. Taken together, these results demonstrate that IκBζ is essential for the activation of NK cells and antiviral host defense responses.

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“…It was then maintained at high levels in Th1 cells, but gradually lost in Th2 cells. Several reported studies have examined histone modifications at the IFN-␥ gene and the Th2 cytokine gene cluster (12,20,24,(37)(38)(39)(40). These studies examined histone modifications in Th1 and Th2 cells differentiated over a short period time.…”

Section: Discussionmentioning

confidence: 99%

Temporal and Spatial Changes of Histone 3 K4 Dimethylation at the IFN-γ Gene during Th1 and Th2 Cell Differentiation

Hamalainen-Laanaya¹,

Kobie²,

Chang

et al. 2007

The Journal of Immunology

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Covalent modification of nucleosomal histones is an important mechanism for cytokine gene regulation in Th1 and Th2 cells. In this study, we analyzed the kinetics of histone H3 K4 dimethylation (H3K4me2) of the IFN-γ gene. Minimal levels of H3K4me2 were found in naive CD4 T cells. After 5 days of differentiation, H3K4me2 levels were elevated in both Th1 and Th2 cells at the −5.3 kb, the promoter, the intronic DNase I hypersensitive sites, and 3′ distal sites including the +9.5 kb and +16 kb sites. Th1 cells maintained high levels of H3K4me2 after longer time of culture. However, in Th2 cells after 14 days, high levels of H3K4me2 were detected only at the −5.3 kb and the promoter, whereas H3K4me2 was lost at the 3′ distal sites and greatly diminished at the DNase I hypersensitive sites. After 28 days, Th2 cells lose H3K4me2 at all sites. Unlike the long-term primary Th2 cells, the Th2 clone D10 showed strong H3K4me2 at the IFN-γ gene with distinctly high levels at the 3′ distal sites. CD4 T cells transgenic for Hlx or infected with T-bet-expressing retrovirus produced IFN-γ and retained high levels of H3K4me2 even after differentiated under Th2 polarizing conditions, suggesting positive roles of these two factors in maintaining high levels of H3K4me2 at the IFN-γ gene.

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Histone hyperacetylated domains across the Ifng gene region in natural killer cells and T cells

Cited by 79 publications

References 37 publications

ATF3 regulates MCMV infection in mice by modulating IFN-γ expression in natural killer cells

ATF3 regulates MCMV infection in mice by modulating IFN-γ expression in natural killer cells

IκBζ is essential for natural killer cell activation in response to IL-12 and IL-18

Temporal and Spatial Changes of Histone 3 K4 Dimethylation at the IFN-γ Gene during Th1 and Th2 Cell Differentiation

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