title: Imprinting of Skin/Inflammation Homing in CD4+ T Cells Is Controlled by DNA Methylation within the Fucosyltransferase 7 Gene.
abstract: E- and P-selectin ligands (E- and P-ligs) guide effector memory T cells into skin and inflamed regions, mediate the inflammatory recruitment of leukocytes, and contribute to the localization of hematopoietic precursor cells. A better understanding of their molecular regulation is therefore of significant interest with regard to therapeutic approaches targeting these pathways. In this study, we examined the transcriptional regulation of fucosyltransferase 7 (FUT7), an enzyme crucial for generation of the glycosylated E- and P-ligs. We found that high expression of the coding gene fut7 in murine CD4+T cells correlates with DNA demethylation within a minimal promoter in skin/inflammation-seeking effector memory T cells. Retinoic acid, a known inducer of the gut-homing phenotype, abrogated the activation-induced demethylation of this region, which contains a cAMP responsive element. Methylation of the promoter or mutation of the cAMP responsive element abolished promoter activity and the binding of CREB, confirming the importance of this region and of its demethylation for fut7 transcription in T cells. Furthermore, studies on human CD4+effector memory T cells confirmed demethylation within FUT7 corresponding to high FUT7 expression. Monocytes showed an even more extensive demethylation of the FUT7 gene whereas hepatocytes, which lack selectin ligand expression, exhibited extensive methylation. In conclusion, we show that DNA demethylation within the fut7 gene controls selectin ligand expression in mice and humans, including the inducible topographic commitment of T cells for skin and inflamed sites.
authors: Experimental Rheumatology, German Rheumatism Research Center, 10117 Berlin, Germany.
authors: Matthias
authors: M
authors: Pink
authors: Experimental Rheumatology, German Rheumatism Research Center, 10117 Berlin, Germany.
authors: Boris A
authors: 0000-0003-0478-1652
authors: BA
authors: Ratsch
authors: Experimental Rheumatology, German Rheumatism Research Center, 10117 Berlin, Germany.
authors: Maibritt
authors: M
authors: Mardahl
authors: Experimental Rheumatology, German Rheumatism Research Center, 10117 Berlin, Germany.
authors: Pawel
authors: 0000-0002-6179-0670
authors: P
authors: Durek
authors: Experimental Rheumatology, German Rheumatism Research Center, 10117 Berlin, Germany.
authors: Julia K
authors: JK
authors: Polansky
authors: Signal Transduction, German Rheumatism Research Center, 10117 Berlin, Germany.
authors: Martin
authors: 0000-0001-5190-9562
authors: M
authors: Karl
authors: Signal Transduction, German Rheumatism Research Center, 10117 Berlin, Germany.
authors: Ria
authors: R
authors: Baumgrass
authors: Institute of Clinical and Laboratory Medicine, University Hospital Regensburg, 93042 Regensburg, Germany.
authors: Stefan
authors: S
authors: Wallner
authors: Leibniz Research Center for Working Environment and Human Factors, 44139 Dortmund, Germany.
authors: Cristina
authors: C
authors: Cadenas
authors: Leibniz Research Center for Working Environment and Human Factors, 44139 Dortmund, Germany.
authors: Kathrin
authors: 0000-0003-0957-0379
authors: K
authors: Gianmoena
authors: Experimental Immunology, Helmholz Center for Infection Research, 38124 Braunschweig, Germany.
authors: Stefan
authors: 0000-0001-9904-4094
authors: S
authors: Floess
authors: Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany.
authors: Wei
authors: W
authors: Chen
authors: Laboratory of Epigenetics, Saarland University, 66123 Saarbrücken, Germany.
authors: Karl
authors: K
authors: Nordstroem
authors: Laboratory of Epigenetics, Saarland University, 66123 Saarbrücken, Germany.
authors: Sascha
authors: S
authors: Tierling
authors: Epiontis GmbH, 12489 Berlin, Germany; and.
authors: Sven
authors: S
authors: Olek
authors: Laboratory of Epigenetics, Saarland University, 66123 Saarbrücken, Germany.
authors: Jörn
authors: 0000-0003-0563-7417
authors: J
authors: Walter
authors: Experimental Rheumatology, German Rheumatism Research Center, 10117 Berlin, Germany.
authors: Alf
authors: 0000-0003-1518-5717
authors: A
authors: Hamann
authors: Medical Clinic for Gastroenterology, Infectious Diseases, and Rheumatology, Charité University Hospital, 12200 Berlin, Germany uta.syrbe@charite.de.
authors: Uta
authors: U
authors: Syrbe
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D019175:DNA Methylation / Q000235:genetics; D005647:Fucosyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; C502597:FUT7 protein, human; D005647:Fucosyltransferases; C514210:fucosyltransferase VII, mouse