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MiR-134-Mbd3 axis regulates the induction of pluripotency.

ABSTRACT: MicroRNAs (miRNAs) are post-transcriptional modulators of gene expression and play an important role in reprogramming process; however, relatively little is known about the underlying regulatory mechanism of miRNAs on how they epigenetically modulate reprogramming and pluripotency. Here, we report that the expression level of microRNA-134 (miR-134) was low in mouse embryonic stem cells (mESCs) but significantly up-regulated during neural differentiation, while down-regulated during the induction of induced pluripotent stem cells (iPSCs) from neural progenitor cells (NPCs). Inhibition of miR-134 by miR-134 sponge promoted the efficiency of reprogramming which also was highly similar to mESCs. On the contrary, up-regulation of miR-134 repressed iPSCs induction. We also found that inhibition of miR-134 promoted the maturation of pre-iPSCs and increased its pluripotency. We also showed that miR-134 can directly target to the pluripotency related factor Methyl-CpG-binding domain protein 3 (Mdb3) 3' untranslated regions (3' UTR) to down-regulate its expression. And Mbd3 was found to promote the induction of iPSCs and could block the repression of reprogramming caused by overexpression of miR-134. This work revealed the critical function of miR-134-Mbd3 axis on regulating reprogramming and pluripotency of iPSCs derived from the NPCs, and might provide an insight into the miR-134-Mbd3 axis on regulating the iPSCs quality for further clinical treatment.

SUBMITTER: Zhang L

PROVIDER: S-EPMC4882991 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBreast cancer (BC) is a prevalent malignancy with complex etiology and varied clinical behavior. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cancer progression, including BC. Among these, lncRNA TDRKH-AS1 has been implicated in several cancers, but its role in BC remains unclear.MethodsWe conducted a comprehensive investigation to elucidate the role of TDRKH-AS1 in BC. Clinical samples were collected from BC patients, and BC cell lines were cultured. Bioinformatics analysis using the starBase database was carried out to assess TDRKH-AS1 expression levels in BC tissue samples. Functional experiments, including knockdown, colony formation, CCK-8, Transwell, and wound-healing assays, were conducted to determine the role of TDRKH-AS1 in BC cell proliferation and invasion. Luciferase reporter and RIP assays were used to examine the interactions between TDRKH-AS1 and miR-134-5p. In addition, the downstream target gene of miR-134-5p, cAMP response element-binding protein 1 (CREB1), was identified and studied using various methods, including RT-qPCR, immunoprecipitation, and rescue experiments. In vivo experiments using mouse tumor xenograft models were conducted to examine the role of TDRKH-AS1 in BC tumorigenesis.ResultsTDRKH-AS1 was found to be significantly upregulated in BC tissues and cell lines. High TDRKH-AS1 expression correlated with advanced BC stages and worse patient outcomes. Knockdown of TDRKH-AS1 led to decreased BC cell proliferation and invasion. Mechanistically, TDRKH-AS1 acted as a sponge for miR-134-5p, thereby reducing the inhibitory effects of miR-134-5p on CREB1 expression. Overexpression of CREB1 partially rescued the effects of TDRKH-AS1 knockdown in BC cells. In vivo studies further confirmed the tumor-promoting role of TDRKH-AS1 in BC.ConclusionsOur study unveiled a novel regulatory axis involving TDRKH-AS1, miR-134-5p, and CREB1 in BC progression. TDRKH-AS1 functioned as an oncogenic lncRNA by promoting BC cell proliferation and invasion through modulation of the miR-134-5p/CREB1 axis. These findings highlighted TDRKH-AS1 as a potential diagnostic biomarker and therapeutic target for BC treatment.

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MiR-134-Mbd3 axis regulates the induction of pluripotency.

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