Differential regulation of P-selectin ligand expression in naive versus memory CD4+ T cells: evidence for epigenetic regulation of involved glycosyltransferase genes

Syrbe, Uta; Jennrich, Silke; Schottelius, Arndt; Richter, Anne; Radbruch, Andreas; Hamann, Alf

doi:10.1182/blood-2003-09-3047

Cited by 44 publications

(35 citation statements)

References 27 publications

(30 reference statements)

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“…Some of the migratory phenotypes become apparently permanently imprinted on differentiation 28,45 and allow a selective delivery of memory populations to specific compartments of the body ("homing"). How stable homing phenotypes are acquired and maintained in the progeny of T and B cells is not well understood.…”

Section: Discussionmentioning

confidence: 99%

“…19 Evidence has been provided in recent years that differentiation of T cells into distinct lineages with stable phenotypes and functions involves epigenetic regulation of critical effector molecules [20][21][22] or lineage-specific transcription factors, such as Foxp3 in Tregs. [23][24][25][26] Only few studies demonstrated that molecules involved in trafficking are subject to epigenetic regulation in T cells 27,28 or cancer cells. 29,30 In addition, a considerable plasticity in the expression of homing receptors has also been observed in some cases.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells

Steinfelder

Floess

Engelbert

et al. 2011

Blood

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CCR6 is a chemokine receptor expressed on Th17 cells and regulatory T cells that is induced by T-cell IntroductionSpecific patterns of chemokine receptor expression ensure an orchestrated migration of leukocytes throughout the body, where immune cells home to their target tissues under both steady-state and inflammatory conditions. The chemokine receptor CCR6 is widely expressed on human blood and tissue leukocytes, including subsets of dendritic cells, CD45RO ϩ effector/memory T cells, CD25 high regulatory T cells (Tregs), naive and memory B cells, NKT cells, and NK cells. [1][2][3][4][5][6] On memory T cells, CCR6 is expressed on a population of autoreactive interleukin-10 (IL-10)-producing cells 7 and subsets of skin-and mucosa-homing cells. Several studies have further shown that CCR6 is consistently expressed on inflammatory IL-17-producing CD4 ϩ T cells, [8][9][10] which are involved in a wide array of adverse inflammatory diseases, such as rheumatoid arthritis, psoriatic disease, inflammatory bowel disease, or encephalopathies in mice and humans. [10][11][12][13][14] More recently, CCR6 was identified as a new risk factor for rheumatoid arthritis; moreover, a nucleotide polymorphism within the CCR6 locus was shown to be associated with susceptibility to rheumatoid arthritis, Graves disease, and Crohn disease. 15,16 CCR6 was shown to play a pivotal role in directing inflammatory and regulatory cells to inflamed tissues or the gut, where the ligand of CCR6 CCL20 is expressed. 13,17,18 Although most chemokine-chemokine receptor interactions are characterized by a high promiscuity, CCR6 binds only CCL20 and ␤-defensins. 1It is widely assumed that the differentiation of T cells into specialized memory subsets also involves the acquisition and stable expression of homing-and chemokine receptor repertoires, allowing tissue-or inflammation-specific trafficking of these subsets. 19 Evidence has been provided in recent years that differentiation of T cells into distinct lineages with stable phenotypes and functions involves epigenetic regulation of critical effector molecules [20][21][22] or lineage-specific transcription factors, such as Foxp3 in Tregs. [23][24][25][26] Only few studies demonstrated that molecules involved in trafficking are subject to epigenetic regulation in T cells 27,28 or cancer cells. 29,30 In addition, a considerable plasticity in the expression of homing receptors has also been observed in some cases. 31,32 Whether this also applies to the expression of CCR6 is not known. In vitro, CCR6 expression can be induced de novo on T-cell receptor (TCR)-stimulated naive T cells by a cocktail of proinflammatory cytokines in combination with transforming growth factor-␤ (TGF-␤). 9 The transcriptional regulation of CCR6 is not well understood; a region with promoter activity has been identified in the mouse CCR6 gene, 33 and overexpression of the transcription factor ROR␥t, the master regulator of Th17 cells, leads to CCR6 expression on human and murine T cells. 10,34 However, whether stable CCR6 expr...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells

Steinfelder

Floess

Engelbert

et al. 2011

Blood

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“…Furthermore, using selective in vitro methylation, we show that the activity of the minimal fut7 promoter is impaired by methylation. Further evidence for the critical role of DNA methylation in control of selectin ligand expression comes from our previous findings that showed 5-aza-deoxycytidine, a DNA methylation inhibitor, enhancing the expression of P-lig in in vitro cultures (15). However, it remains to be elucidated whether demethylation in the fut7 locus in T cells relies on inhibition of methylation on the newly generated DNA strain during cell division mediated by DNA methyltransferases or on active demethylation involving ten-eleven translocation proteins, which convert 5mC to 5-hydroxymethylcytosine.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we showed that the induction of selectin ligands in CD4 + T cells requires cell division, which is considered a window for epigenetic changes. Moreover, artificial demethylation with 5-aza-deoxycytidine in T cell cultures increased P-lig expression, suggesting that DNA methylation controls selectin ligand expression in CD4 + T cells (15).…”

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confidence: 99%

Imprinting of Skin/Inflammation Homing in CD4+ T Cells Is Controlled by DNA Methylation within the Fucosyltransferase 7 Gene

Pink

Ratsch

Mardahl

et al. 2016

The Journal of Immunology

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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.

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“…FUT3 overexpression in gastric cells also depends on hypomethylation of its promoter [17]. A similar observation is reported in FUT7 expression [18]. Although increases in the fucosylation level and FUT4 expression were observed in MDA-MB-231 cells treated with a methyltransferase inhibitor, zebularine [19], it is unclear whether FUT4 expression level is directly correlated with the methylation status of the FUT4 promoter.…”

Section: Discussionmentioning

confidence: 61%

Differential fucosyltransferase IV expression in squamous carcinoma cells is regulated by promoter methylation

Li¹,

Tong²,

Liu

et al. 2012

Cellular and Molecular Biology Letters

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Enhanced fucosyltransferase IV (FUT4) expression correlates with increased tumor malignancy in many carcinomas. However, little is known about the regulation of FUT4 expression, and whether FUT4 expression is influenced by the methylation status of the FUT4 promoter is unclear. In this study, we demonstrated that FUT4 expression is negatively correlated with the methylation degree of a CpG island in the FUT4 promoter, suggesting that the methylation status of FUT4 promoter regulates the expression of FUT4. The results indicate that manipulating the methylation status of the FUT4 promoter to regulate FUT4 expression may be a novel approach in the treatment of malignant tumors.

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Differential regulation of P-selectin ligand expression in naive versus memory CD4+ T cells: evidence for epigenetic regulation of involved glycosyltransferase genes

Cited by 44 publications

References 27 publications

Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells

Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells

Imprinting of Skin/Inflammation Homing in CD4+ T Cells Is Controlled by DNA Methylation within the Fucosyltransferase 7 Gene

Differential fucosyltransferase IV expression in squamous carcinoma cells is regulated by promoter methylation

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