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

Abstract

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 analyse 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.

Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis

“…Consistent with our results, a previous study showed that PAK1, a downstream effector of PIAS3 that has been demonstrated in the present work, also regulated MMP-13 expression in RA FLSs (44). SENP1, which served as a deSUMOylation enzyme, participated in the regulation of MMP-1 expression in RA FLSs (45). These results therefore suggest that one of the mechanisms of PIAS3 involved in pathogenesis of RA is regulating MMPs production.…”

Epigenetic regulation of proMMP-1 expression in the HT1080 human fibrosarcoma cell line

“…It has been established that the proMMP-1 gene expression requires chromatin remodeling in part via histone posttranslational modifications (18)(19)(20)(21)(22). A previous study showed that proMMP-1 gene expression induced by TPA in T98G cells involved a dynamic and ordered recruitment of enzymes allowing H3/H4 acetylation, H3K4 di-and trimethylation, H3S10 phosphorylation and chromatin opening (22).…”

Regulated Transcription of Human Matrix Metalloproteinase 13 (MMP13) and Interleukin-1β (IL1B) Genes in Chondrocytes Depends on Methylation of Specific Proximal Promoter CpG Sites

“…Moreover, only a few reports have addressed how methylation of individual CpG sites influences the promoter activity of a specific gene (6,10,11), and the relative contributions of the methylation status of each individual CpG site to the transcriptional regulation of a given gene in vivo remain largely unexplored. In addition, although epigenetic gene regulation has been broadly investigated in other contexts, little is known about the specific impact of this mechanism of gene control in musculoskeletal diseases (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”