Abstract
Long noncoding RNAs (lncRNAs) are emerging as new players in gene regulation, but whether lncRNAs operate in the processing of miRNA primary transcript is unclear. Also, whether lncRNAs are involved in the regulation of the mitochondrial network remains to be elucidated. Here, we report that a long noncoding RNA, named mitochondrial dynamic related lncRNA (MDRL), affects the processing of miR-484 primary transcript in nucleus and regulates the mitochondrial network by targeting miR-361 and miR-484. The results showed that miR-361 that predominantly located in nucleus can directly bind to primary transcript of miR-484 (pri-miR-484) and prevent its processing by Drosha into pre-miR-484. miR-361 is able to regulate mitochondrial fission and apoptosis by regulating miR-484 levels. In exploring the underlying molecular mechanism by which miR-361 is regulated, we identified MDRL and demonstrated that it could directly bind to miR-361 and downregulate its expression levels, which promotes the processing of pri-miR-484. MDRL inhibits mitochondrial fission and apoptosis by downregulating miR-361, which in turn relieves inhibition of miR-484 processing by miR-361. Our present study reveals a novel regulating model of mitochondrial fission program which is composed of MDRL, miR-361 and miR-484. Our work not only expands the function of the lncRNA pathway in gene regulation but also establishes a new mechanism for controlling miRNA expression.
Highlights
Long non-coding RNAs are non-protein coding transcripts longer than 200 nucleotides
We identified mitochondrial dynamic related lncRNA (MDRL) which can act as an endogenous ‘sponge’ that directly binds to miR-361 and downregulates its expression levels. miR-361 can directly bind to primary transcript of miR-484 and prevent its processing by Drosha into pre-miR-484
Our present work revealed that miR-361 directly binds to primiR-484 and prevents its processing by Drosha into pre-miR-484. miR-361 is able to regulate mitochondrial fission and apoptosis, and this regulatory effects on mitochondrial fission and apoptosis is through targeting miR-484
Summary
Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. LncRNAs can act as antisense transcripts or as decoy for splicing factors leading to splicing malfunctioning [7,8], and can act as a competing endogenous RNA (ceRNA) in mouse and human myoblasts [9]. It is not yet clear whether lncRNA can be involved in the processing of pri-miRNA and the regulation of mitochondrial network. Recent studies have identified the functional role of miRNA in numerous facets of cardiac biology, including the control of myocyte growth, contractility, fibrosis, angiogenesis, heart failure, and myocardial infarction, providing potential therapeutic targets for heart disease. To prevent and reverse myocardial infarction, it is critical to identify those miRNAs that are able to regulate myocardial infarction and to characterize their signal transduction pathways in the apoptotic cascades
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