Core 2 β1,6-N-acetylglucosaminyltransferase-I, crucial for P-selectin ligand expression is controlled by a distal enhancer regulated by STAT4 and T-bet in CD4+T helper cells 1

Mardahl, Maibritt; Schröter, Micha F.; Engelbert, Dirk; Pink, Matthias; Sperandio, Markus; Hamann, Alf und Syrbe, Uta (2016): Core 2 β1,6-N-acetylglucosaminyltransferase-I, crucial for P-selectin ligand expression is controlled by a distal enhancer regulated by STAT4 and T-bet in CD4+T helper cells 1. In: Molecular Immunology, Bd. 77: S. 132-140

Abstract

P-selectin ligands (P-ligs) support the recruitment of lymphocytes into inflamed tissues. Binding to P-selectin is mediated by oligosaccharide groups synthesized by means of several glycosyltransferases including core 2 beta 1,6-N-acetylglucosaminyltransferase-I (C2G1cNAcT-I), encoded by the gene Gcntl. Using Gcnt1(-1-) Th1 cells, we show that C2GIcNAcT-I is crucial for inflammatory T cell homing in vivo. To understand the molecular regulation of Gcntl in CD4* T helper cells, we performed ChIP-on-chip experiments across the Gcntl locus assessing the chromatin structure in P-lig-expressing versus non expressing CD4(+) T cells. This identified a distal region about 20 kb upstream of the promoter where the presence of a H3K27me3 mark correlated with Gcntl repression. This region possessed IL-12-dependent enhancer activity in reporter assays, in accordance with preferential IL-12-dependent induction of Gcntl in vitro. STAT4 and T-bet cooperated in control of the enhancer activity. Deficiency in either one resulted in drastically reduced Gcntl mRNA expression in differentiated Th1 cells. While both STAT4 and T-bet were bound to the enhancer early after activation only T-bet binding persisted throughout the expansion phase after TCR signal cessation. This suggests sequential action of STAT4 and T-bet at the enhancer. In summary, we show that Gcntl transcription and subsequent P-lig induction in Th1 cells is governed by binding of STAT4 and T-bet to a distal enhancer and further regulated by epigenetic marks such as H3K27me3. (C) 2016 Elsevier Ltd. All rights reserved.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0161-5890
• Sprache: Englisch