A Lipopolysaccharide-Specific Enhancer Complex Involving Ets, Elk-1, Sp1, and CREB Binding Protein and p300 Is Recruited to the Tumor Necrosis Factor Alpha Promoter In Vivo

Tsai, Eunice Y.; Falvo, James V.; Tsytsykova, Alla V.; Barczak, Amy K.; Reimold, Andreas M.; Glimcher, Laurie H.; Fenton, Matthew J.; Gordon, David C.; Dunn, Ian F.; Goldfeld, Anne E.

doi:10.1128/mcb.20.16.6084-6094.2000

Cited by 242 publications

(279 citation statements)

References 58 publications

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“…Furthermore, we were unable to detect a DH site in intron 3 in LPS-or mock-stimulated murine monocytic J774 cells (R. Barthel and A. E. Goldfeld, unpublished). Here we also show cell type-specific DH sites in the proximal promoter, in sequences between the TSS and the ATG, and in the 3ЈUTR, regions that have previously been shown to play important functional roles in TNF-␣ gene regulation (1,3,4,9,11,12). Consistent with our findings, we note that constitutive DH sites have been identified in the IL-2 gene that are cell lineage specific and that distinguish IL-2 producer and nonproducer T cells (13).…”

Section: Discussionsupporting

confidence: 90%

“…Previous studies have demonstrated the important functional roles of the proximal promoter, the region from the TSS to the ATG and the 3ЈUTR in TNF-␣ gene regulation (3,4,9). To test whether intron 3 might also contain a regulatory element, we examined the effect of the addition of intron 3 on the regulation of a TNF-␣ luciferase reporter gene.…”

Section: Resultsmentioning

confidence: 99%

“…T he primary control point of TNF-␣ gene transcription and protein production is the regulation of transcriptional initiation of the gene and involves the recruitment of cell type-and inducer-specific higher order structures, or enhanceosomes, to the promoter (1)(2)(3)(4). Intriguingly, the sequences contained in enhanceosome formation form a phylogenetic footprint, or a region of conserved sequences throughout the primate lineage (5) (A. Baena and A. E. Goldfeld, unpublished observations).…”

Section: T Cell-specific Expression Of the Human Tnf-␣ Gene Involves mentioning

confidence: 99%

“…Using a five-nucleotide sliding window that was moved along the entire human TNF-␣ genomic sequence, the total number of pairwise differences between the human sequence and representatives of seven non-human primate species at each nucleotide position was quantified, and we identified striking regions of complete conservation, or phylogenetic footprints, particularly in intron 3. Notably, DNase I hypersensitivity (DH) 3 analysis and dimethylsulfate (DMS) in vivo footprinting of three of these regions revealed that they are both accessible to DNase I and make DNAprotein contacts in a cell type-specific manner. Consistent with these results, intron 3, which contains a constitutive DH site in Jurkat T cells, but not in THP-1 monocytic cells, displays multiple T cell-specific in vivo footprints and enhances the activity of a TNF-␣ promoter reporter gene in Jurkat cells, but not in THP-1 cells.…”

Section: T Cell-specific Expression Of the Human Tnf-␣ Gene Involves mentioning

confidence: 99%

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T Cell-Specific Expression of the Human TNF-α Gene Involves a Functional and Highly Conserved Chromatin Signature in Intron 3

Barthel

Goldfeld

2003

The Journal of Immunology

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Using a phylogenetic approach, we identified highly conserved sequences within intron 3 of the human TNF-α gene. These sequences form cell type-specific DNase I hypersensitivity sites and display cell type-specific DNA-protein contacts in in vivo genomic footprints. Consistent with these results, intron 3 confers specific activity upon a TNF-α reporter gene in Jurkat T cells, but not THP-1 monocytic cells. Thus, using a combinatorial approach of phylogenetic analysis, DNase I hypersensitivity analysis, in vivo footprinting, and transfection analysis, we demonstrate that intronic regulatory elements are involved in the cell type-specific regulation of TNF-α gene expression.

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: T Cell-specific Expression Of the Human Tnf-␣ Gene Involves mentioning

confidence: 99%

Section: T Cell-specific Expression Of the Human Tnf-␣ Gene Involves mentioning

confidence: 99%

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T Cell-Specific Expression of the Human TNF-α Gene Involves a Functional and Highly Conserved Chromatin Signature in Intron 3

Barthel

Goldfeld

2003

The Journal of Immunology

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“…These results are consistent with the idea that the CREB binding site (Ϫ1267 to Ϫ1260) plays a role in the LPS-mediated mTLR2 induction. It has recently been reported that CREB plays a role in the TNF-␣ mRNA induction by LPS in macrophages (28). In another report, it has been revealed that CREB is activated by LPS through p38 stress-activated protein kinase and is involved in the up-regulation of CD80, CD83, and CD86 (31).…”

Section: Discussionmentioning

confidence: 99%

NF-κB and STAT5 Play Important Roles in the Regulation of Mouse Toll-Like Receptor 2 Gene Expression

Musikacharoen

Matsuguchi

Kikuchi

et al. 2001

The Journal of Immunology

123

107

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Toll-like receptor 2 (TLR2) is involved in the innate immunity by recognizing various bacterial components. We have previously reported that TLR2 gene expression is rapidly induced by LPS or inflammatory cytokines in macrophages, and by TCR engagement or IL-2/IL-15 stimulation in T cells. Here, to investigate the mechanisms governing TLR2 transcription, we cloned the 5′ upstream region of the mouse TLR2 (mTLR2) gene and mapped its transcriptional start site. The 5′ upstream region of the mTLR2 gene contains two NF-κB, two CCAAT/enhancer binding protein, one cAMP response element-binding protein, and one STAT consensus sequences. In mouse macrophage cell lines, deletion of both NF-κB sites caused the complete loss of mTLR2 promoter responsiveness to TNF-α. NF-κB sites were also important but not absolutely necessary for LPS-mediated mTLR2 promoter activation. In T cell lines, mTLR2 responsiveness to IL-15 was abrogated by the 3′ NF-κB mutation, whereas 5′ NF-κB showed no functional significance. The STAT binding site also seemed to contribute, as the deletion of this sequence significantly reduced the IL-15-mediated mTLR2 promoter activation. EMSAs confirmed nuclear protein binding to both NF-κB sites in macrophages following LPS and TNF-α stimulation and to the 3′ NF-κB site in T cells after IL-15 treatment. Thus, NF-κB activation is important but differently involved in the regulation of mTLR2 gene expression in macrophages and T cells following LPS or cytokine stimulation.

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Dynamic changes in chromatin conformation at theTNFtranscription start site inThelper lymphocyte subsets

et al. 2013

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Tumor necrosis factor (TNF) is one of the key primary response genes in the immuneKeywords: Chromatin conformation r Th cells r T lymphocyte r TNF r Transcription start site Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionTumor necrosis factor (TNF) is a pleiotropic cytokine expressed by various types of lymphoid and myeloid cells, including T cells, B cells, NK cells, monocytes, macrophages, DCs, and mast cells (reviewed in [1,2]). TNF is involved in development, homeostasis, and activation of the immune system [3][4][5][6][7][8]. Physiological functions mediated by TNF depend on the cellular sources and the molecular form of this cytokine [9][10][11]. In particular, TNF produced by macrophages and T cells plays different roles in immune and inflammatory reactions [9,10]. TNF is the primary response gene in macrophages where it has a permissive chromatin conformation [12,13]. Even without stimulation, the proximal TNF Correspondence: Dr. Yury V. Shebzukhov e-mail: shebzukhov@drfz.de promoter and transcription start site (TSS) have an open chromatin configuration in primary monocytes and macrophages and in the majority of tested myelomonocytic cell lines [14][15][16][17][18][19][20][21][22]. Various T-cell subsets produce different amounts of TNF in correlation with their pathophysiological potential [23]. Earlier studies [24] as well as recent advances in high-throughput analysis of DNaseI chromatin accessibility indicate that the proximal part of the TNF promoter in T cells is open (Supporting Information Fig. 1); however, in contrast to macrophages, the TSS of TNF in T cells acquires open chromatin conformation only after activation or polarization under Th1 or Th17 (where Th is T helper) conditions. TNF gene expression in T cells is regulated by the NFAT and AP-1 families of transcription factors; in particular, activation of the proximal TNF promoter region involves functional interactions with the transcription factors NFATc2 and c-Jun [25][26][27][28][29][30][31]. Numerous reports also supported the involvement of the NF-κB family members in transcriptional regulation of the TNF gene inwww.eji-journal.eu 252Yury V. Shebzukhov et al. Eur. J. Immunol. 2014. 44: 251-264 macrophages, in spite of the lack of canonical high-affinity NF-κB binding sites within the proximal TNF promoter [32][33][34][35][36][37][38][39]. However, specific role of NF-κB family members in regulation of the TNF gene is still being debated ([1, 2] and Discussion section). In murine T cells, members of the NF-κB family were shown to bind to the distal part of the TNF promoter [40] and to the enhancer element immediately downstream of the TNF gene (3 -TNF enhancer) [24], but the functional significance of these interactions is not clear.Here, we demonstrate the difference in chromatin structure around TNF TSS between T cells and macrophages. We further show that active forms of c-Jun and NFATc2 transcription factors are involved in chromatin remodeling oc...

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A Lipopolysaccharide-Specific Enhancer Complex Involving Ets, Elk-1, Sp1, and CREB Binding Protein and p300 Is Recruited to the Tumor Necrosis Factor Alpha Promoter In Vivo

Cited by 242 publications

References 58 publications

T Cell-Specific Expression of the Human TNF-α Gene Involves a Functional and Highly Conserved Chromatin Signature in Intron 3

T Cell-Specific Expression of the Human TNF-α Gene Involves a Functional and Highly Conserved Chromatin Signature in Intron 3

NF-κB and STAT5 Play Important Roles in the Regulation of Mouse Toll-Like Receptor 2 Gene Expression

Dynamic changes in chromatin conformation at theTNFtranscription start site inThelper lymphocyte subsets

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