Abstract
MiR-133a is a muscle-enriched miRNA, which plays a key role for proper skeletal and cardiac muscle function via regulation of transduction cascades, including the Wnt signalling. MiR-133a modulates its targets via canonical mRNA repression, a process that has been largely demonstrated to occur within the cytoplasm. However, recent evidence has shown that miRNAs play additional roles in other sub-cellular compartments, such as nuclei. Here, we show that miR-133a translocates to the nucleus of cardiac cells following inactivation of the canonical Wnt pathway. The nuclear miR-133a/AGO2 complex binds to a complementary miR-133a target site within the promoter of the de novo DNA methyltransferase 3B (Dnmt3b) gene, leading to its transcriptional repression, which is mediated by DNMT3B itself. Altogether, these data show an unconventional role of miR-133a that upon its relocalization to the nucleus is responsible for epigenetic repression of its target gene Dnmt3b via a DNMT3B self-regulatory negative feedback loop.
Highlights
The multifactorial nature of the cardiac system tightly relies on the dynamic and regulated interplay between signalling pathways and the modulation of associated effector molecules
Our results suggest that miR-133a recruits AGO2 to the PBMS within the DNA methyltransferase 3B (Dnmt3b) promoter, thereby regulating gene transcription through induction of epigenetic changes associated with transcriptional repression
We showed that in the Wnt off-state, the cardiac enriched miR-133a relocalizes to the nucleus where it directly regulates the transcription of the Dnmt3b epigenetic gene
Summary
The multifactorial nature of the cardiac system tightly relies on the dynamic and regulated interplay between signalling pathways and the modulation of associated effector molecules. In this contest, of relevant importance is the canonical Wnt signalling, which has been demonstrated to tightly regulate multiple aspects of both cardiac development and maintenance of adult heart homeostasis[1]. Activation of the cascade (Wnt on-state) stabilizes β-catenin, which in turn translocates to the nucleus, where it binds to members of the lymphoid enhancement factor/T-cell factor (LEF/TCF) family of transcription factors. Β-catenin binding converts LEF/TCF factors from repressors to activators, thereby initiating cell-specific gene transcription patterns[2]. Through binding to a specific miR-133a target site within the promoter region of the de novo DNA methyltransferase 3B gene (Dnmt3b), nuclear AGO2-bound miR-133a initiates an epigenetic control of Dnmt3b gene transcription repression, which enrols DNMT3B for a self-regulatory circuit
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