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Imprinting of skin/inflammation homing in CD4+ T cells is controlled by DNA methylation within the fucosyltransferase 7 gene

Item Type:Article
Title:Imprinting of skin/inflammation homing in CD4+ T cells is controlled by DNA methylation within the fucosyltransferase 7 gene
Creators Name:Pink, M. and Ratsch, B.A. and Mardahl, M. and Durek, P. and Polansky, J.K. and Karl, M. and Baumgrass, R. and Wallner, S. and Cadenas, C. and Gianmoena, K. and Floess, S. and Chen, W. and Nordstroem, K. and Tierling, S. and Olek, S. and Walter, J. and Hamann, A. and Syrbe, U.
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.
Keywords:CD4-Positive T-Lymphocytes, Cultured Cells, DNA Methylation, Fucosyltransferases, Inbred BALB C Mice, Inflammation, Messenger RNA, Skin, Animals, Mice
Source:Journal of Immunology
Publisher:American Association of Immunologists
Page Range:3406-3414
Date:15 October 2016
Official Publication:https://doi.org/10.4049/jimmunol.1502434
PubMed:View item in PubMed

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