Epigenetics and rheumatoid arthritis: the role of SENP1 in the regulation of MMP-1 expression.
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.
Maciejewska-Rodrigues
Hanna
H
Center of Experimental Rheumatology, University Hospital Zurich, Gloriastrasse 23-25, Zurich 8091, Switzerland. Hanna.Maciejewska@usz.ch <Hanna.Maciejewska@usz.ch>
Karouzakis
Emmanuel
E
Strietholt
Simon
S
Hemmatazad
Hossein
H
Neidhart
Michel
M
Ospelt
Caroline
C
Gay
Renate E
RE
Michel
Beat A
BA
Pap
Thomas
T
Gay
Steffen
S
Jüngel
Astrid
A
D000107:Acetylation; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases; D004285:Dogs; D010450:Endopeptidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000473:pathology; D019076:Transgenes / Q000235:genetics
D006657:Histones; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases; D020781:Matrix Metalloproteinase 1; C400300:HDAC4 protein, human; D006655:Histone Deacetylases