MicroRNA-29b/142-5p contribute to the pathogenesis of biliary atresia by regulating the IFN-? gene.

ABSTRACT: Biliary atresia is one of the most common liver disease in infancy. The cause and pathogenesis remain largely unknown. This study aimed to investigate the potential regulatory effect of miR-29b/142-5p on IFN-? gene methylation. miRNAs microarray was performed on four pairs of liver and blood specimens from biliary atresia and choledochal cysts. We found the overexpression of miR-142-5p and mRNA level of DNA methyltransferase (DNMT) 1, and miR-29b and DNMT3a/DNMT3b were significantly negatively correlated in biliary atresia livers. Meanwhile, the methylation of the LINE-1, ALU and SAT2 repetitive sequences and the IFN-? promoter was lower, but the expression of IFN-? was upregulated. After transfected with DNMTs siRNAs, downregulation of DNMTs exerted a significant hypomethylating effect on the repetitive sequences, which led to upregulation of IFN-? in Jurkat cells. The direct interactions between miR-29b and DNMT3a/3b, and miR-142-5p and DNMT1 were identified using luciferase reporter assays. By transfecting mimics of miR-29b/142-5p into Jurkat cells, we found overexpression of miR-29b/142-5p markedly suppressed expression of DNMTs. Furthermore, the methylation of repetitive sequences and the IFN-? promoter region were remarkably downregulated, and with elevated IFN-? expression. After transfecting the miRNA inhibitors, the levels of DNMTs and the methylation of the IFN-? gene promoter region was upregulated, while levels of IFN-? were markedly suppressed. Our study suggested that miRNA-29b/142-5p overexpression and targeted inhibition of DNMTs expression resulted in decreased overall gene methylation and overexpression of the methylation-sensitive IFN-? gene.

SUBMITTER: Yang Y 

PROVIDER: S-EPMC5945737 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature