title: cAMP-responsive element modulator α (CREMα) contributes to decreased Notch-1 expression in T cells from patients with active systemic lupus erythematosus (SLE).
abstract: Notch signaling constitutes an evolutionarily conserved pathway that transduces signals between neighboring cells and determines major decisions in cell proliferation, survival, and differentiation. Notch signaling has been shown to play a pivotal role during T cell lineage determination. T lymphocytes from patients with systemic lupus erythematosus (SLE) display a severely altered phenotype with several molecular and functional aberrations, including defective capacities to up-regulate Notch-1 receptor expression upon T cell receptor activation. Here, we demonstrate that basal Notch-1 expression is decreased in T cells from active SLE patients at the mRNA and protein levels in various T cell subpopulations. Notch-1 transcript numbers inversely correlate with disease activity in SLE patients. We provide evidence that both enhanced histone H3 methylation and CpG DNA methylation of the human Notch-1 promoter contribute to decreased Notch-1 expression in SLE T cells. Previous data from our group identified cAMP-responsive element modulator α (CREMα), which is up-regulated in SLE T cells, as a key regulator of epigenetic patterns and gene transcription, e.g. that of IL2 and IL17 genes. In this study, we observed increased CREMα binding to the Notch-1 promoter, which eventually resulted in significantly reduced Notch-1 promoter activity and gene transcription. Notably, decreased Notch-1 levels were associated with elevated IL-17A levels. Our data suggest a role for Notch-1 in SLE immunopathogenesis, and for the first time, we present molecular mechanisms that mediate dysregulated Notch-1 expression in SLE T cells.
authors.affiliation: Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rauen
authors.forename: Alexandros P
authors.initials: AP
authors.lastname: Grammatikos
authors.forename: Christian M
authors.initials: CM
authors.lastname: Hedrich
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.forename: Klaus
authors.initials: K
authors.lastname: Tenbrock
authors.forename: Kim
authors.initials: K
authors.lastname: Ohl
authors.forename: Vasileios C
authors.initials: VC
authors.lastname: Kyttaris
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002462:Cell Membrane / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D019169:Jurkat Cells; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C497410:CREM protein, human; D006657:Histones; D020381:Interleukin-17; C497761:NOTCH1 protein, human; D012333:RNA, Messenger; D051881:Receptor, Notch1; D051786:Cyclic AMP Response Element Modulator