Journal
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
Volume 1859, Issue 2, Pages 223-234Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagrm.2015.11.003
Keywords
Treg; GARP; DNA methylation; Gene transcription; Altemative promoter; Transcriptional interference
Categories
Funding
- Deutsche Forschungsgemeinschaft [SK59/4-1, Schu 786/2-5, Schu 786/8-1]
- DFG [SFB571, GK1202]
- Federal Ministry of Education and Research of Germany [OIEC100913, OIEC1008H]
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Alternative promoter usage has been proposed as a mechanism regulating transcriptional and translational diversity in highly elaborated systems like the immune system in humans. Here, we report that transcription of human glycoprotein A repetitions predominant (GARP) in regulatory CD4 T cells (Tregs) is tightly regulated by two alternative promoters. An intragenic promoter contains several CpGs and acts as a weak promoter that is demethylated and initiates transcription Treg-specifically. The strong up-stream promoter containing a CpG-island is, in contrast, fully demethylated throughout tissues. Transcriptional activity of the strong promoter was surprisingly down-regulated upon demethylation of the weak promoter. This demethylation-induced transcriptional attenuation regulated the magnitude of GARP expression and correlated with disease activity in rheumatoid arthritis. Treg-specific GARP transcription was initiated by synergistic interaction of forkhead box protein 3 (Foxp3) with nuclear factor of activated T cells (NFAT) and was underpinned by permissive chromatin remodeling caused by release of the H3K4 demethylase, PLU-1. Our findings describe a novel function of alternative promoters in regulating the extent of transcription. Moreover, since GARP functions as a transporter of transforming growth factor beta (TGF beta), a cytokine with broad pleiotropic traits, GARP transcriptional attenuation by alternative promoters might provide a mechanism regulating peripheral TGF beta to avoid unwanted harmful effects. (C) 2015 Elsevier B.V. All rights reserved.
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