Epigenetics and rheumatoid arthritis: The role of SENP1 in the regulation of MMP-1 expression

Autor: Hanna Maciejewska-Rodrigues, Emmanuel Karouzakis, Simon Strietholt, Hossein Hemmatazad, Michel Neidhart, Caroline Ospelt, Renate E. Gay, Beat A. Michel, Thomas Pap, Steffen Gay, Astrid Jüngel
Přispěvatelé: University of Zurich, Maciejewska Rodrigues, H
Jazyk: angličtina
Rok vydání: 2010
Předmět:
SENP1
Immunology
610 Medicine & health
Histone Deacetylases
Cell Line
Epigenesis
Genetic
Arthritis
Rheumatoid
Histones
Histone H4
03 medical and health sciences
Dogs
0302 clinical medicine
Downregulation and upregulation
Endopeptidases
Animals
Humans
Immunology and Allergy
Neoplasm Invasiveness
Transgenes
Epigenetics
Cloning
Molecular
RNA
Small Interfering
Promoter Regions
Genetic
030304 developmental biology
030203 arthritis & rheumatology
0303 health sciences
2403 Immunology
biology
Synovial Membrane
10051 Rheumatology Clinic and Institute of Physical Medicine
Acetylation
Fibroblasts
HDAC4
Sumoylation Pathway
Molecular biology
Repressor Proteins
Cysteine Endopeptidases
Histone
10076 Center for Integrative Human Physiology
Cancer research
biology.protein
2723 Immunology and Allergy
570 Life sciences
Matrix Metalloproteinase 1
Zdroj: Journal of Autoimmunity
Journal of Autoimmunity; Vol 35
Popis: 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.
Databáze: OpenAIRE
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