title: Promoter hypomethylation results in increased expression of protein phosphatase 2A in T cells from patients with systemic lupus erythematosus.
abstract: The catalytic subunit α isoform of protein phosphatase 2A (PP2Acα) activity, protein, and mRNA have been found increased in systemic lupus erythematosus (SLE) T cells and to contribute to decreased IL-2 production. The PP2Acα promoter activity is controlled epigenetically through the methylation of a CpG within a cAMP response element (CRE) motif defined by its promoter. We considered that hypomethylation may account for the increased expression of PP2Acα in patients with SLE. Using bisulfite sequencing, we found that SLE T cells displayed decreased DNA methylation in the promoter region compared with normal T cells. More importantly, we found that the CRE-defined CpG, which binds p-CREB, is significantly less methylated in SLE compared with normal T cells, and the levels of methylation correlated with decreased amounts of DNA methyltransferase 1 transcripts. Methylation intensity correlated inversely with levels of PP2Acα mRNA and SLE disease activity. Chromatin immunoprecipitation assays revealed more binding of p-CREB to the CRE site in SLE T cells, resulting in increased expression of PP2Acα. We propose that PP2Acα represents a new methylation-sensitive gene that, like the previously reported CD70 and CD11a, contributes to the pathogenesis of SLE.
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Katsue
authors.initials: K
authors.lastname: Sunahori
authors.forename: Yuang-Taung
authors.initials: YT
authors.lastname: Juang
authors.forename: Vasileios C
authors.initials: VC
authors.lastname: Kyttaris
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D000328:Adult; D001483:Base Sequence; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000276:immunology*; D054648:Protein Phosphatase 2 / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2