DNMT1 activates the canonical Wnt signaling in rheumatoid arthritis model rats via a crucial functional crosstalk between miR-152 and the DNMT1, MeCP2.
Int Immunopharmacol
; 28(1): 344-53, 2015 Sep.
Article
em En
| MEDLINE
| ID: mdl-26093272
ABSTRACT
In previous study, we identified that microRNA (miR)-152 expression was down-regulated in RA model rats, and overexpression of miR-152 inhibited the canonical Wnt signaling through the DNA methyltransferase (DNMT1) inhibition. However, the exact molecular mechanisms of DNMT1 were unclear. In this work, we investigate whether DNMT1 affects the pathogenesis of RA model rats and targets the miR-152 promoter. The effects of DNMT1 on the canonical Wnt signaling, the pathogenesis of RA model rats and the SFRP1 expression were detected by the real time qPCR, Western blotting, ELISA, MTT and viable cell number assay. The interaction between miR-152 and DNMT1, methyl CpG binding protein 2 (MeCP2) was investigated by real time qPCR and chromatin immunoprecipitation (ChIP). Our results revealed that increased DNMT1 activated the canonical Wnt signaling could not only by targeting SFRP4 may also by SFRP1 in RA model rats. Furthermore, treatment of DNMT1 inhibitor, 5-aza-2'-deoxycytidine (5-azadC), or knockdown of DNMT1, or knockdown of MeCP2 led to increased miR-152 expression by reversion of its promoter hypermethylation, DNMT1 and MeCP2 binding to the CpG islands of miR-152 promoter. Interestingly, it is proved a synergistic inhibition effect of DNMT1 and MeCP2 in this process. Moreover, overexpression of miR-152 could inhibit DNMT1 expression and result in a decrease of DNMT1 and MeCP2 binding to miR-152 promoter, and inhibition of miR-152 expression would reverse it. These observations demonstrate a crucial functional crosstalk between miR-152 and the DNMT1, MeCP2 by a double-negative circuit involved in the pathogenesis of RA model rats.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Artrite Reumatoide
/
MicroRNAs
/
DNA (Citosina-5-)-Metiltransferases
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Proteína 2 de Ligação a Metil-CpG
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Via de Sinalização Wnt
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Int Immunopharmacol
Assunto da revista:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
China