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Abstract Number: 419

Epigenome Analysis of Rheumatoid Arthritis Synovial Fibroblasts Revealed TBX-5 As a Novel Transcription Factor in Chemokine Regulation

Emmanuel Karouzakis1, Michelle Trenkmann2, Renate E. Gay1, Beat A. Michel1, Steffen Gay1 and Michel Neidhart1, 1Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland, 2Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology (ZIHP), Zurich, Switzerland

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: chemokines, Epigenetics, Fibroblasts, pathogenesis and synovial cells, rheumatoid arthritis, synovial fluid

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Session Information

Title: Rheumatoid Arthritis - Human Etiology and Pathogenisis

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Changes in DNA methylation and histone marks have been associated with diseases such as cancer, rheumatoid arthritis (RA) and systemic lupus erythematosus. Previously, we performed methylation immunoprecipitation (MeDIP) in combination with human promoter arrays and identified TBX5 as a differentially methylated gene in RA synovial fibroblasts (SF). Now, we want to further examine its role in the pathogenesis of RA and identify specific TBX5 gene targets.

Methods:

Methylation immunoprecipitation assay was used to analyze DNA extracts from OASF (n=5) and RASF (n=7) cell cultures. Bisulfite sequencing was used to confirm the MeDIP results. Transient transfections were done in OASF cell cultures with a TBX5 overexpression vector. RNA and cDNA were prepared and used to hybridize an Affymetrix human microarray. The microarray expression array was confirmed by quantitative SYBR PCR in OASF cultures (n=7). DAVID bioinformatics software was used to functional annotate the microarray data.

Results:

The TBX5 gene was significantly more methylated in OASF than RASF, as shown by MeDIP assay (OASF 17±2.9 and RASF 5±3.5 fold enrichment, p<0.04, n=6). The MeDIP results were confirmed by bisulfite sequencing of the TBX5 promoter. TBX5 transcripts were significantly more expressed in RASF than OASF (RASF dCt: 16.0 ± 0.6; OASF dCt: 19±0.3, p<0.005, n=8). In addition, Western blot showed that the TBX5 protein was expressed in RASF, but not in OASF. Overexpression of TBX5 in OASF revealed 640 genes commonly up regulated from 1.2 to 3-fold. Analysis of these genes by DAVID bioinformatics tool identified that the chemokines IL8, CXCL2 and CCL20 were common targets of TBX5 in OASF. The expression of chemokines was significantly upregulated in seven different OASF cell cultures (IL8: 2 fold change ±0.9, CXCL2: 1.97 fold change±0.9, CCL20:2.07±0.8, p<0.05).

Conclusion:

Promoter specific DNA hypomethylation and an open chromatin are responsible for the intrinsically up-regulated TBX5 expression in RASF. TBX5 may be a novel regulator of chemotaxis thereby associated with the ability of RASF to attract inflammatory cells to the synovium.


Disclosure:

E. Karouzakis,

IAR, IMI-BTCure, Novartis-Stiftung,

2;

M. Trenkmann,

Masterswitch-FP7,IMI-BTCure,IAR,

2;

R. E. Gay,

Masterswitch-FP7 and her institution,

2;

B. A. Michel,

his institution,

3;

S. Gay,

IAR and his institution,

2;

M. Neidhart,

his institution,

3.

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