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Expression and function of EZH2 in synovial fibroblasts: epigenetic repression of the Wnt inhibitor SFRP1 in rheumatoid arthritis


Trenkmann, M; Brock, M; Gay, R E; Kolling, C; Speich, R; Michel, B A; Gay, S; Huber, L C (2011). Expression and function of EZH2 in synovial fibroblasts: epigenetic repression of the Wnt inhibitor SFRP1 in rheumatoid arthritis. Annals of the Rheumatic Diseases, 70(8):1482-1488.

Abstract

OBJECTIVES: /st> To study the expression, regulation and function of the histone methyltransferase enhancer of zeste homologue 2 (EZH2) in synovial fibroblasts (SF) from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: /st> SF were obtained from RA and OA patients undergoing joint surgery. Expression levels were assessed by quantitative real-time PCR and western blot. Kinase inhibitors and reporter gene assays were employed to study signalling pathways. Functional analyses included EZH2 overexpression by plasmid transfection and gene silencing by small interfering RNA. Chromatin immunoprecipitation assay was used to analyse histone methylation within distinct promoter regions. RESULTS: /st> By studying the expression and function of EZH2 in SF the authors found that EZH2 is overexpressed in rheumatoid arthritis synovial fibroblasts (RASF) and further induced by tumour necrosis factor alpha through the nuclear factor kappa B and Jun kinase pathways. As a target gene of EZH2 the authors identified secreted frizzled-related protein 1 (SFRP1), an inhibitor of Wnt signalling, which is associated with the activation of RASF, and show that SFRP1 expression correlates with the occupation of its promoter with activating and silencing histone marks. CONCLUSIONS: /st> These data strongly suggest that the chronic inflammatory environment of the RA joint induces EZH2 and thus might cause changes in the epigenetic programmes of SF.

Abstract

OBJECTIVES: /st> To study the expression, regulation and function of the histone methyltransferase enhancer of zeste homologue 2 (EZH2) in synovial fibroblasts (SF) from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: /st> SF were obtained from RA and OA patients undergoing joint surgery. Expression levels were assessed by quantitative real-time PCR and western blot. Kinase inhibitors and reporter gene assays were employed to study signalling pathways. Functional analyses included EZH2 overexpression by plasmid transfection and gene silencing by small interfering RNA. Chromatin immunoprecipitation assay was used to analyse histone methylation within distinct promoter regions. RESULTS: /st> By studying the expression and function of EZH2 in SF the authors found that EZH2 is overexpressed in rheumatoid arthritis synovial fibroblasts (RASF) and further induced by tumour necrosis factor alpha through the nuclear factor kappa B and Jun kinase pathways. As a target gene of EZH2 the authors identified secreted frizzled-related protein 1 (SFRP1), an inhibitor of Wnt signalling, which is associated with the activation of RASF, and show that SFRP1 expression correlates with the occupation of its promoter with activating and silencing histone marks. CONCLUSIONS: /st> These data strongly suggest that the chronic inflammatory environment of the RA joint induces EZH2 and thus might cause changes in the epigenetic programmes of SF.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic and Policlinic for Internal Medicine
04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2011
Deposited On:23 May 2011 14:16
Last Modified:05 Apr 2016 14:55
Publisher:BMJ Publishing Group
ISSN:0003-4967
Publisher DOI:https://doi.org/10.1136/ard.2010.143040
PubMed ID:21515604

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