Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-28729
Maciejewska-Rodrigues, H; Karouzakis, E; Strietholt, S; Hemmatazad, H; Neidhart, M; Ospelt, C; Gay, R E; Michel, B A; Pap, T; Gay, S; Jüngel, A (2010). Epigenetics and rheumatoid arthritis: The role of SENP1 in the regulation of MMP-1 expression. Journal of Autoimmunity, 35(1):15-22.
The aggressive phenotype of RA synovial fibroblasts (RASF) is characterised by the increased expression of matrix metalloproteinase (MMP)-1 as well as the small ubiquitin like modifier (SUMO)-1 and decreased expression of SUMO-specific protease SENP1. Since we showed an increased activity of acetyltransferases in this autoimmune disease, we wanted to analyze whether this affects the expression of MMP-1 and can be reversed by the reconstitution of SENP1. In RASF, the acetylation of histone H4 was significantly increased in the distal region of the MMP-1 promoter by 274 +/- 36% compared to OASF. Most interestingly, overexpression of SENP1 in RASF decreased acetylation specifically in this region by 51 +/- 0.5% and globally by 73 +/- 11%. Furthermore, the overexpression of SENP1 resulted in a downregulation of MMP-1 at both the mRNA (58 +/- 7%) and protein levels (28 +/- 6%), significantly reduced the invasiveness of RASF (from 34 +/- 9% to 2 +/- 2%) and led to an accumulation of histone deacetylase 4 (HDAC4) on the MMP-1 promoter (197 +/- 36%). Interestingly, SENP1 failed to modulate the expression of MMP-1 in the cells silenced for HDAC4. This is the first study linking the SUMOylation pathway and the production of MMP-1 to an epigenetic control mechanism mediated through histone acetylation which has a functional consequence for the invasiveness of RASF.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Center for Integrative Human Physiology|
04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Date:||15 August 2010|
|Deposited On:||29 Jan 2010 15:22|
|Last Modified:||27 Nov 2013 23:03|
|Citations:||Web of Science®. Times cited: 25|
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