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.

Single-Cell RNA Sequencing Reveals Tissue Compartment-Specific Plasticity of Mycosis Fungoides Tumor Cells

“…Importantly, malignant cells of the peripheral blood expressed the skin-homing receptor CLA as shown by flow cytometry ( Figure S4 ), consistent with corresponding gene upregulation of both SELPLG and the fucosyltransferase FUT7 ( 50 ) ( Figure 6D ), indicating their retained capability to home to the skin ( 51 , 52 ).…”

Endothelial E-selectin inhibition improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance

“…The changes in cell surface glycosylation observed with oncogenic transformation are likely mediated by epigenetic mechanisms. Inflammatory mediators (such as TNF-α 48 and G-CSF 49 ) have previously been reported to lead to increased ST3GAL4, FUT4, and FUT7 expression, which are largely regulated by repressive promoter methylation 50,51 . Thus, it is tempting to speculate that the altered glycosylation (and increase in E-selectin binding potential) on malignant cells is associated with the epigenetic changes in DNA methylation and histone modulation that occurs during oncogenesis, possibly re-enforced by tumorassociated inflammation.…”

T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy

“…77 – 79 CLA bears the tetrasaccharide moiety, sLe X , which is recognized by the HECA-452 mAb, and its biosynthesis is catalyzed in part by FTIV and VII, of which the latter enzyme can be induced by IL-2, IL-7, IL-12, TGF-β, Ag-priming, and promoter demethylation and is suppressed by IL-4 and retinoic acid. 30 , 71 , 80 – 84 Knockout mice lacking FTIV and FTVII fail to generate T eff cells that home to skin. 30 Skin inflammation upregulates cognate ligands on dermal postcapillary microvessels recognized by skin-tropic receptors, including E-selectin (in humans and other primates), and both E- and P-selectin (in non-primate mammals), chemokines CCL17 (CCR4 receptor) and CCL27 (CCR10 receptor), ICAM-1 (LFA-1 receptor) and VCAM-1 (VLA-4 receptor).…”