Methylation of an intragenic alternative promoter regulates transcription of GARP

S Haupt, VSA Söntgerath, J Leipe… - … et Biophysica Acta (BBA …, 2016 - Elsevier
S Haupt, VSA Söntgerath, J Leipe, H Schulze-Koops, A Skapenko
Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms, 2016Elsevier
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 …
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.
Elsevier