Chromatin profiling across the human tumour necrosis factor gene locus reveals a complex, cell type-specific landscape with novel regulatory elements

Taylor, Jennifer; Wicks, Kate; Vandiedonck, Claire; Knight, Julian C.

doi:10.1093/nar/gkn444

Cited by 21 publications

(43 citation statements)

References 70 publications

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“…Notably, a transactivator of transcription (Tat) protein from HIV-1 subtype E (HIV-1 TH64 Tat), which specifically inhibited TNF transcription, also inhibited p/CAF recruitment to the TNF promoter and decreased levels of histone H3 acetylation and GCN5 recruitment [184]. Enrichment of acetylated histone H3 and H4 was also reported in the vicinity of the TNF promoter in PMA/ionomycin-stimulated Jurkat cells [190]. …”

Section: Epigenetic Regulation Of Tnf Transcriptionmentioning

confidence: 99%

“…Histone modifications that are typically associated with gene derepression and transcription have been detected at the TNF promoter. Mono-, di-, and trimethylation of lysine 4 of histone H3 (H3K4) has been observed at the TNF promoter following LPS or TNF stimulation of THP-1 cells and PMA/ionomycin stimulation of Jurkat cells [116, 186, 190]. Phosphorylation of serine 10 of histone H3 (H3S10) has been observed at the TNF promoter in THP-1 cells, but not primary human dendritic cells, following LPS stimulation [123, 191].…”

Section: Epigenetic Regulation Of Tnf Transcriptionmentioning

confidence: 99%

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Transcriptional Control of the TNF Gene

Falvo¹,

Tsytsykova²,

Goldfeld³

2010

Current Directions in Autoimmunity

220

170

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The cytokine TNF is a critical mediator of immune and inflammatory responses. The TNF gene is an immediate early gene, rapidly transcribed in a variety of cell types following exposure to a broad range of pathogens and signals of inflammation and stress. Regulation of TNF gene expression at the transcriptional level is cell type- and stimulus-specific, involving the recruitment of distinct sets of transcription factors to a compact and modular promoter region. In this review, we describe our current understanding of the mechanisms through which TNF transcription is specifically activated by a variety of extracellular stimuli in multiple cell types, including T cells, B cells, macrophages, mast cells, dendritic cells, and fibroblasts. We discuss the role of nuclear factor of activated T cells and other transcription factors and coactivators in enhanceosome formation, as well as the contradictory evidence for a role for nuclear factor κB as a classical activator of the TNF gene. We describe the impact of evolutionarily conserved cis-regulatory DNA motifs in the TNF locus upon TNF gene transcription, in contrast to the neutral effect of single nucleotide polymorphisms. We also assess the regulatory role of chromatin organization, epigenetic modifications, and long-range chromosomal interactions at the TNF locus.

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Section: Epigenetic Regulation Of Tnf Transcriptionmentioning

confidence: 99%

Section: Epigenetic Regulation Of Tnf Transcriptionmentioning

confidence: 99%

Transcriptional Control of the TNF Gene

Falvo¹,

Tsytsykova²,

Goldfeld³

2010

Current Directions in Autoimmunity

220

170

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“…35,36 Moreover, the TNF 5Ј upstream and 3Ј downstream regions have been shown to physically interact by forming an intrachromosomal loop, the topology that could promote the reinitiation of transcription. 35 This model may be of a particular relevance to TNF expression by MDDCs, in which a cooperative action of RelA and IRF5 at both the 5Ј upstream and downstream regions appears to be essential for maintaining TNF gene transcription over a prolonged period of time.…”

Section: Irf5 In Tnf Secretion By Dcs 4427mentioning

confidence: 99%

IRF5 is required for late-phase TNF secretion by human dendritic cells

Krausgruber

Saliba

Ryzhakov

et al. 2010

Blood

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Spatially and temporally controlled expression of inflammatory mediators is critical for an appropriate immune response. In this study, we define the role for interferon regulatory factor 5 (IRF5) in secretion of tumor necrosis factor (TNF) by human dendritic cells (DCs). We demonstrate that DCs but not macrophages have high levels of IRF5 protein, and that IRF5 is responsible for the late-phase expression of TNF, which is absent in macrophages. Sustained TNF secretion is essential for robust T IntroductionTumor necrosis factor (TNF) is one of the major cytokines responsible for effector immune functions. As well as playing a central role in host defense against infection, TNF is a major factor in the pathogenesis of chronic inflammatory disease such as rheumatoid arthritis (RA). Consequently, tightly controlled regulation of its expression is critical for an appropriate immune response. This occurs at the transcriptional and posttranscriptional levels, with transcriptional regulation showing specificity for both stimulus and cell type. 1 The NF-B family of transcription factors (TFs) plays a major role in transcriptional up-regulation of the TNF gene by lipopolysaccharide (LPS) in both mouse and human myeloid cells. [2][3][4][5] Regulation of transcription for many immune genes in response to Toll-like receptor (TLR) signaling involves a combination of NF-B and interferon regulatory factor (IRF) factors. 6 IRFs appear to provide a mechanism for conferring signal specificity to a variety of target gene subsets, with IRF3 being essential for type I interferon (IFN) response, 7 and IRF5 playing a key role in induction of proinflammatory cytokines, including TNF, Consequently, IRF5 Ϫ/Ϫ mice show resistance to lethal shock induced by CpG-B or LPS. 8 Unlike other IRF family members, IRF5 contains 2 nuclear localization signals (NLSs), 1 in the N-terminus and the other in the C-terminus of the protein. This results in low levels of nuclear translocation and therefore weak trans-activation activity of IRF5, even in unstimulated cells. 9 The molecular pathways leading to IRF5 activation are not well understood, but it was shown that TLR signaling induces the formation of MyD88-IRF5-TRAF6 complexes, 8 and is probably followed by phosphorylation of specific sites within the IRF5 C-terminal autoinhibitory domain. 10 Human IRF5 is expressed as multiple spliced variants with distinct cell type-specific expression, cellular localization, differential regulation, and dissimilar functions. 11 Moreover, genetic polymorphisms in the IRF5 gene leading to expression of several unique isoforms have been implicated in autoimmune diseases, including systemic lupus erythematosis (SLE), RA and Sjogren syndrome. 12-15 IRF5 mRNA expression has been detected in B cells, dendritic cells (DCs), monocytes, and natural killer (NK) cells but not in T cells, 11 yet little is known about the IRF5 protein expression in these cells.Here, we demonstrate that human monocytes acquire high levels of IRF5 protein during differentiation into monocyte-d...

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“…Moreover, distal hypersensitive (DH) elements upstream and downstream of the TNF transcription start site (TSS) have been identified in the TNF/LT locus. A subset of these DH sites also varies by cell type (Barthel et al 2003, Tsytsykova et al, 2007, Taylor et al, 2008; Biglione et al, 2011). For example, DH sites ~9 kb upstream and ~3 kb downstream of the murine gene act as NFATp-dependent enhancers in T cells and participate in activation-induced intrachromosomal interactions with the promoter (Tsytsykova et al, 2007), while a myeloid-specific DH site ~7 kb upstream of the TSS functions as a matrix attachment region (Biglione et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

A Distal Locus Element Mediates IFN-γ Priming of Lipopolysaccharide-Stimulated TNF Gene Expression

2014

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SUMMARY IFN-γ priming sensitizes monocytes/macrophages to lipopolysaccharide (LPS) stimulation, resulting in augmented expression of a set of genes including TNF. Here, we demonstrate that IFN-γ priming of LPS-stimulated TNF transcription requires a distal TNF/LT locus element 8 kb upstream of the TNF transcription start site (hHS-8). IFN-γ stimulation leads to increased DNase I accessibility of hHS-8 and its recruitment of IRF1, and subsequent LPS stimulation enhances H3K27 acetylation and induces enhancer RNA synthesis at hHS-8. Ablation of IRF1 or targeting the hHS-8 IRF1 binding site in vivo with Cas9 linked to the KRAB repressive domain abolishes IFN-γ priming while LPS induction of the gene is unaffected. Thus, IFN-γ poises a distal enhancer in the TNF/LT locus by chromatin remodeling and IRF1 recruitment, which then drives enhanced TNF gene expression in response to a secondary TLR stimulus.

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Chromatin profiling across the human tumour necrosis factor gene locus reveals a complex, cell type-specific landscape with novel regulatory elements

Cited by 21 publications

References 70 publications

Transcriptional Control of the TNF Gene

Transcriptional Control of the TNF Gene

IRF5 is required for late-phase TNF secretion by human dendritic cells

A Distal Locus Element Mediates IFN-γ Priming of Lipopolysaccharide-Stimulated TNF Gene Expression

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