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Biochim Biophys Acta. 2016 Feb;1859(2):223-34. doi: 10.1016/j.bbagrm.2015.11.003. Epub 2015 Nov 14.

Methylation of an intragenic alternative promoter regulates transcription of GARP.

Author information

1
Division of Rheumatology and Clinical Immunology, Medizinische Klinik und Poliklinik IV, University of Munich, 80336 Munich, Germany.

Abstract

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 β (TGFβ), a cytokine with broad pleiotropic traits, GARP transcriptional attenuation by alternative promoters might provide a mechanism regulating peripheral TGFβ to avoid unwanted harmful effects.

KEYWORDS:

Alternative promoter; DNA methylation; GARP; Gene transcription; Transcriptional interference; Treg

PMID:
26584734
DOI:
10.1016/j.bbagrm.2015.11.003
[Indexed for MEDLINE]

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