RFX1 regulates CD70 and CD11a expression in lupus T cells by recruiting the histone methyltransferase SUV39H1.

Abstract

INTRODUCTION:

Regulatory factor X-box 1 (RFX1) can interact with DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1), and RFX1 down-regulation contributes to DNA hypomethylation and histone H3 hyperacetylation at the cluster of differentiation (CD) 11a and CD70 promoters in CD4(+) T cells of patients with systemic lupus erythematosus (SLE). This leads to CD11a and CD70 overexpression, thereby triggering autoimmune responses. In order to provide more insight into the epigenetic mechanisms leading to the deregulation of autoimmune-related genes in SLE, we asked whether RFX1 is involved in regulating histone 3 lysine 9 (H3K9) tri-methylation at the CD11a and CD70 promoters in SLE CD4(+) T cells.

METHODS:

CD4(+) T cell samples were isolated from 15 SLE patients and 15 healthy controls. H3K9 tri-methylation levels were measured by chromatin immunoprecipitation (ChIP) and real-time quantitative PCR. CD4(+) T cells were transfected with plasmids using the Human T cell Nucleofector Kit. RFX1 and histone methyltransferase suppressor of variegation 3-9 (Drosophila) homolog 1 (SUV39H1) interaction was determined by co-immunoprecipation (co-IP) and Western blot and immunofluorescence staining. CD11a and CD70 mRNA levels were measured by real-time RT-PCR.

RESULTS:

H3K9 tri-methylation levels were significantly reduced within the CD11a and CD70 promoter regions in SLE CD4(+) T cells. RFX1 co-immunoprecipitated with SUV39H1 at the CD11a and CD70 promoters in healthy control CD4(+) T cells. Overexpressing or knocking-down RFX1 revealed that RFX1 expression correlated with H3K9 tri-methylation levels, as well as CD11a and CD70 expression levels in CD4(+) T cells.

CONCLUSIONS:

RFX1 recruits SUV39H1 to the promoter regions of the CD11a and CD70 genes in CD4(+) T cells, thereby regulating local H3K9 tri-methylation levels. These findings shed further light on the central role of RFX1 down-regulation in the epigenetic de-repression of auto-immune genes in SLE.

• Authors: Ming Zhao, Xiaoyan Wu, Qing Zhang, Shuangyan Luo, Gongping Liang, Yuwen Su, Yixin Tan, Qianjin Lu
• Journal: Arthritis research & therapy (Arthritis Res Ther) Vol. 12 Issue 6 Pg. R227 ( 2010) ISSN: 1478-6362 [Electronic] England
• PMID: 21192791 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD11a Antigen
• CD27 Ligand
• CD70 protein, human
• DNA-Binding Proteins
• Histones
• RFX1 protein, human
• Regulatory Factor X Transcription Factors
• Regulatory Factor X1
• Repressor Proteins
• Transcription Factors
• SUV39H1 protein, human
• Methyltransferases

Topics

• Adult
• Autoimmunity (genetics, immunology)
• Blotting, Western
• CD11a Antigen (biosynthesis, genetics, immunology)
• CD27 Ligand (biosynthesis, genetics, immunology)
• Chromatin Immunoprecipitation
• DNA Methylation
• DNA-Binding Proteins (immunology, metabolism)
• Epigenesis, Genetic
• Female
• Fluorescent Antibody Technique
• Gene Expression Regulation
• Histones (metabolism)
• Humans
• Immunoprecipitation
• Lupus Erythematosus, Systemic (genetics, immunology, metabolism)
• Male
• Methyltransferases (genetics, immunology, metabolism)
• Promoter Regions, Genetic
• Regulatory Factor X Transcription Factors
• Regulatory Factor X1
• Repressor Proteins (genetics, immunology, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• T-Lymphocytes (immunology, metabolism)
• Transcription Factors (immunology, metabolism)