title: Histone modifications and methyl-CpG-binding domain protein levels at the TNFSF7 (CD70) promoter in SLE CD4+ T cells.
abstract: In systemic lupus erythematosus (SLE), T lymphocytes overexpress CD70 (TNFSF7 gene), leading to the synthesis of autoreactive IgGs. CD70 upregulation in SLE CD4(+) T cells is associated with hypomethylation of TNFSF7 promoter. In this study, we explored histone modifications in the TNFSF7 promoter region in SLE CD4(+) T cells, and characterized the effects of a DNA methyltransferase inhibitor (5-azaC) and a histone deacetylase inhibitor (TSA) on CD70 expression. We found that CD70 mRNA was significantly increased in active lupus CD4(+) T cells, and in control cells treated with 5-azaC, TSA, or both. Histone H3 acetylation and dimethylated H3 lysine 4 (H3K4me2) levels were significantly elevated in patients with lupus, and both factors correlated positively with disease activity. MeCP2 protein levels within the TNFSF7 promoter decreased in patients with active lupus. Treatment of CD4+ T cells with 5-azaC alone significantly raised H3K4 dimethyl levels at the TNFSF7 locus. TSA treatment significantly increased H3 and H4 acetylation levels, as well as levels of H3K4 dimethylation at the TNFSF7 locus. Treatment with 5-azaC plus TSA enhanced H3 acetylation levels. These findings indicate that aberrant histone modifications within the TNFSF7 promoter may contribute to the development of lupus by increasing CD70 expression in CD4(+) T cells.
authors.affiliation: Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, Hunan, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.forename: X
authors.initials: X
authors.lastname: Qiu
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
authors.forename: J
authors.initials: J
authors.lastname: Yuan
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: Q
authors.initials: Q
authors.lastname: Zhong
authors.forename: M
authors.initials: M
authors.lastname: Zhao
authors.forename: Q
authors.initials: Q
authors.lastname: Lu
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001374:Azacitidine / Q000494:pharmacology; D053282:CD27 Ligand / Q000235:genetics* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D055815:Young Adult
chemical_list: D053282:CD27 Ligand; C505771:CD70 protein, human; D004791:Enzyme Inhibitors; D006657:Histones; D051783:Methyl-CpG-Binding Protein 2; D008239:Lysine; D001374:Azacitidine