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Nuclear factor of activated T cells 1 (NFAT1)-induced permissive chromatin modification facilitates nuclear factor-?B (NF-?B)-mediated interleukin-9 (IL-9) transactivation.

ABSTRACT: IL-9 regulates diverse inflammatory immune responses. Although the functional importance of IL-9 has been investigated in various pathophysiological conditions, molecular mechanisms by which TCR stimulation induced IL-9 gene expression are still unclear. In this study, we investigated the functional importance of the NFAT1 and NF-?B (p65) in IL-9 gene transcription in CD4(+) T cells. In vivo binding of NFAT1 and NF-?B (p65) to the IL-9 promoter was observed. NFAT1 binding induced a transcriptionally active chromatin configuration at the IL-9 promoter locus, whereas NF-?B (p65) binding transactivated the IL-9 promoter. Mouse deficient in NFAT1 shows a significant down-regulation of IL-9 expression that resulted from an inaccessible chromatin configuration at the IL-9 promoter. In parallel, knockdown of NF-?B (p65) also resulted in reduced IL-9 expression. In this process, NFAT1 plays a pivotal role as a core protein that creates an accessible platform for the assembly of transcription activators. The presence of NFAT1 correlates with recruitment of NF-?B (p65), p300, and active histone markers on the IL-9 promoter, resulting in a transcriptionally competent promoter. NFAT1 deficiency significantly reduced the recruitment of the above activation complex to the IL-9 promoter. In summary, our data suggest that functional cooperation of NFAT1 and NF-?B synergistically enhances IL-9 transcription in CD4(+) T cells.

SUBMITTER: Jash A

PROVIDER: S-EPMC3346086 | biostudies-other | 2012 May

REPOSITORIES: biostudies-other

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Nuclear factor of activated T cells 1 (NFAT1)-induced permissive chromatin modification facilitates nuclear factor-κB (NF-κB)-mediated interleukin-9 (IL-9) transactivation.

Jash Arijita A Sahoo Anupama A Kim Gi-Cheon GC Chae Chang-Suk CS Hwang Ji-Sun JS Kim Jung-Eun JE Im Sin-Hyeog SH

The Journal of biological chemistry 20120315 19

IL-9 regulates diverse inflammatory immune responses. Although the functional importance of IL-9 has been investigated in various pathophysiological conditions, molecular mechanisms by which TCR stimulation induced IL-9 gene expression are still unclear. In this study, we investigated the functional importance of the NFAT1 and NF-κB (p65) in IL-9 gene transcription in CD4(+) T cells. In vivo binding of NFAT1 and NF-κB (p65) to the IL-9 promoter was observed. NFAT1 binding induced a transcription ...[more]

PMID: 22427656

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Project description:Platelet-derived growth factors are a family of potent mitogens and chemoattractants for fibroblasts and other cells of mesenchymal origin. Platelet-derived growth factor (PDGF) dimeric ligands (composed of A-, B-, C-, and D-chains) exert their biological activity through high affinity interactions with cell surface receptor subunits (alpha and beta). PDGF-receptor-alpha is widely implicated in the pathogenesis of hyperplastic fibrotic disease, yet the molecular mechanisms controlling its expression in response to injury are poorly understood. Here we show that PDGF-R alpha expression is induced in fibroblasts by mechanical injury and interleukin (IL)-1beta, which was abolished by neutralizing IL-1beta antibodies in the culture supernatant or inhibitors of NF-kappaB. Chromatin immunoprecipitation and electrophoretic mobility shift assays revealed the existence of a new NF-kappaB binding site at -531/-521 bp in the PDGF-R alpha promoter. We have recently shown that ATF-4 is also induced by injury (Malabanan, K. P., Kanellakis, P., Bobik, A., and Khachigian, L. M. (2008) Circ. Res. 103, 378-387), and we demonstrate here that ATF-4 binds a novel element -259/-254 and stimulates PDGF-R alpha transcription. ATF-4 and NF-kappaB interact, occupy the PDGF-R alpha promoter, and induce PDGF-R alpha transcription in a cooperative manner. IL-1beta facilitates the dissociation of histone deacetylase (HDAC)-1/2 from the PDGF-R alpha promoter, whereas the HDAC inhibitors suberoylanilide hydroxamic acid and trichostatin A potentiate IL-1beta induction of PDGF-R alpha transcription. These findings, taken together, demonstrate that injury stimulates IL-1beta secretion by fibroblasts, which activates NF-kappaB and ATF-4 and stimulates interaction with the PDGF-R alpha promoter, triggering PDGF-R alpha transcription. Physical and functional interactions between NF-kappaB and ATF-4 have not been reported in any gene. This is also the first report of HDAC regulation of PDGF-R alpha transcription.

Dataset Information

Nuclear factor of activated T cells 1 (NFAT1)-induced permissive chromatin modification facilitates nuclear factor-?B (NF-?B)-mediated interleukin-9 (IL-9) transactivation.

Publications

Nuclear factor of activated T cells 1 (NFAT1)-induced permissive chromatin modification facilitates nuclear factor-κB (NF-κB)-mediated interleukin-9 (IL-9) transactivation.

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