Epigenetics and SLE: RFX1 downregulation causes CD11a and CD70 overexpression by altering epigenetic modifications in lupus CD4+ T cells.
DNA demethylation and histone hyperacetylation of CD11a and CD70 regulatory regions contribute to the development of autoreactivity and autoantibody overstimulation in CD4(+) T cells of patients with systemic lupus erythematosus (SLE). However, the mechanisms causing these changes remain largely unknown. We report that the expression and activity of the transcription factor RFX1 are decreased in SLE CD4(+) T cells. We demonstrate that RFX1 affects DNA methylation and histone acetylation in CD4(+) T cells by recruiting the co-repressors DNMT1 and HDAC1 to the CD11a and CD70 promoters, and thereby represses their expression. Reducing RFX1 in CD4(+) T cells is sufficient to cause lupus-like T and B cell hyperactivity, whereas overexpressing RFX1 suppresses T cell reactivity. These findings reveal a crucial role for RFX1 in regulating the epigenetic status of T cells, and demonstrate that autoimmune responses in SLE are due in part to RFX1 downregulation.
Zhao
Ming
M
Department of Dermatology, Epigenetic Research Center, Second Xiangya Hospital, Central South University, #139 Renmin Middle Rd, Changsha, Hunan 410011, PR China.
Sun
Yimin
Y
Gao
Fei
F
Wu
Xiaoyan
X
Tang
Jinling
J
Yin
Heng
H
Luo
Yongqi
Y
Richardson
Bruce
B
Lu
Qianjin
Q
D000107:Acetylation; D000328:Adult; D000818:Animals; D040881:CD11a Antigen / Q000096:biosynthesis* / Q000235:genetics; D053282:CD27 Ligand / Q000096:biosynthesis* / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D000071716:Regulatory Factor X1; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D040881:CD11a Antigen; D053282:CD27 Ligand; D004268:DNA-Binding Proteins; C000605537:RFX1 protein, human; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D000071716:Regulatory Factor X1; D014157:Transcription Factors; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1