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Abstract
Recent studies demonstrate the functions of long non-coding RNAs (lncRNAs) in mediating gene expression at the transcriptional or translational level. Our previous study identified a Sirt1 antisense (AS) lncRNA transcribed from the Sirt1 AS strand. However, its role and regulatory mechanism is still unknown in myogenesis. Here, functional analyses showed that Sirt1 AS lncRNA overexpression promoted myoblast proliferation, but inhibited differentiation. Mechanistically, Sirt1 AS lncRNA was found to activate its sense gene, Sirt1. The luciferase assay provided evidences that Sirt1 AS lncRNA interacted with Sirt1 3′ UTR and rescued Sirt1 transcriptional suppression by competing with miR-34a. In addition, RNA stability assay showed that Sirt1 AS lncRNA prolonged Sirt1 mRNA half-life from 2 to 10 h. Ribonuclease protection assay further indicated that it fully bound to Sirt1 mRNA in the myoblast cytoplasm. Moreover, Sirt1 AS overexpression led to less mouse weight than the control because of less lean mass and greater levels of Sirt1, whereas the fat mass and levels of miR-34a were not altered. Based on the findings, a novel regulatory mechanism was found that Sirt1 AS lncRNA preferably interacted with Sirt1 mRNA forming RNA duplex to promote Sirt1 translation by competing with miR-34a, inhibiting muscle formation.
Highlights
Long noncoding RNA has been shown to play important functional roles as regulators of gene expression through the recruitment of the complex epigenetic machinery that dictates distinctive chromatin signatures involved in active transcription and translation
Our findings provided a novel regulatory mechanism: it was that Sirt[1] AS long non-coding RNAs (lncRNAs) preferably interacted with Sirt[1] mRNA forming RNA duplex by competing with miR-34a to inhibit muscle formation
To examine the expression patterns of Sirt[1] AS lncRNA, Sirt[1] mRNA and miR-34a, their levels were detected by qPCR or western blotting during myoblast proliferation, respectively
Summary
Long noncoding RNA (lncRNA) has been shown to play important functional roles as regulators of gene expression through the recruitment of the complex epigenetic machinery that dictates distinctive chromatin signatures involved in active transcription and translation. LncRNA regulates key function genes by numbers of mechanisms at different levels, including transcriptional, post-transcriptional and epigenetic[7]. At the post-transcriptional level, the muscle-specific lncRNA (linc-MD1) ‘‘sponges’’ miR-133 and miR-135 to regulate the expression of transcription factors mastermind-like protein 1 (MAML1) and myocyte-specific enhancer factor 2C (MEF2C) to activate muscle-specific gene expression[11]. LncRNAs including metastasis-associated lung adenocarcinoma transcript 1 (Malat1), H19 and gene trap locus 2-maternally expressed gene 3 (Gtl2-Meg3) interacted with polycomb repressive complex 2 (PRC2) to modulate their target genes, resulting in myogenesis[12,13,14]. We have identified a novel NAT that corresponds to Sirtuin type 1 (Sirt1) AS lncRNA
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