Abstract
Here we show that a major muscle specific isoform of the murine LINC complex protein SUN1 is required for efficient muscle regeneration. The nucleoplasmic domain of the isoform specifically binds to and inhibits Drosha, a key component of the microprocessor complex required for miRNA synthesis. Comparison of the miRNA profiles between wildtype and SUN1 null myotubes identified a cluster of miRNAs encoded by a non-translated retrotransposon-like one antisense (Rtl1as) transcript that are decreased in the WT myoblasts due to SUN1 inhibition of Drosha. One of these miRNAs miR-127 inhibits the translation of the Rtl1 sense transcript, that encodes the retrotransposon-like one protein (RTL1), which is also required for muscle regeneration and is expressed in regenerating/dystrophic muscle. The LINC complex may therefore regulate gene expression during muscle regeneration by controlling miRNA processing. This provides new insights into the molecular pathology underlying muscular dystrophies and how the LINC complex may regulate mechanosignaling.
Highlights
In recent years the nuclear envelope (NE) and lamina have attracted much interest due to the identification of a significant number of diseases that are associated with mutations in component proteins of the NE and especially the A-type lamins (Burke and Stewart, 2014)
We focused on which Sun1 isoforms were expressed in adult skeletal muscle and found their expression changes during myogenesis
Nine miRNAs were identified that differed significantly in their expression levels between WT and Sun1–/– with some showing increased and others decreased levels of expression in the Sun1–/– myotubes (Figure 4B). Of these nine miRNAs, we chose to focus on three that significantly increased in the Sun1–/– myotubes, miRNAs, À127–3 p, À434–3 p, À431–3 p, as they are all encoded as a cluster within the Rtl1 antisense transcript (Rtl1as) (Figure 4C panel one and lower diagram)
Summary
In recent years the nuclear envelope (NE) and lamina have attracted much interest due to the identification of a significant number of diseases that are associated with mutations in component proteins of the NE and especially the A-type lamins (Burke and Stewart, 2014). SUN1 is required for Piwi interacting RNAs (piRNAs) synthesis in the germline (Chi et al, 2009) Besides these cellular functions, the lamins, members of the LINC complex and in other NE proteins, such as emerin are of clinical importance in that mutations result in a range of congenital diseases (Worman, 2012). We show that both Sun, and Rtl, are required for efficient muscle regeneration in adult mice and that SUN1’s interaction with Drosha may regulate RTL1 levels by controlling the synthesis of a key miRNA modulating RTL1 translation These findings identify a pathway by which the LINC complex may regulate protein expression necessary for efficient muscle regeneration by acting as a microprocessor regulatory component
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