Abstract
Skeletal muscle possesses an outstanding capacity to regenerate upon injury due to the adult muscle stem cell (MuSC) activity. This ability requires the proper balance between MuSC expansion and differentiation, which is critical for muscle homeostasis and contributes, if deregulated, to muscle diseases. Here, we functionally characterize a novel chromatin-associated long noncoding RNA (lncRNA), Lnc-Rewind, which is expressed in murine MuSCs and conserved in human. We find that, in mouse, Lnc-Rewind acts as an epigenetic regulator of MuSC proliferation and expansion by influencing the expression of skeletal muscle genes and several components of the WNT (Wingless-INT) signalling pathway. Among them, we identified the nearby Wnt7b gene as a direct Lnc-Rewind target. We show that Lnc-Rewind interacts with the G9a histone lysine methyltransferase and mediates the in cis repression of Wnt7b by H3K9me2 deposition. Overall, these findings provide novel insights into the epigenetic regulation of adult muscle stem cells fate by lncRNAs.
Highlights
The transcriptional output of all organisms was recently found to be more complex than originally imagined, as the majority of the genomic content is pervasively transcribed into a diverse range of regulatory short and long non-protein coding RNAs (Abugessaisa et al, 2017; Carninci et al, 2005; Cipriano and Ballarino, 2018)
Lnc-Rewind is a conserved chromatin-associated long noncoding RNA (lncRNA) expressed in satellite cells
We focused on Lnc-Rewind, which is a lncRNA enriched in proliferating myoblasts and overlapping pre-Mirlet7c-2 and pre-Mirlet7b genomic loci (Figure 1A)
Summary
The transcriptional output of all organisms was recently found to be more complex than originally imagined, as the majority of the genomic content is pervasively transcribed into a diverse range of regulatory short and long non-protein coding RNAs (ncRNAs) (Abugessaisa et al, 2017; Carninci et al, 2005; Cipriano and Ballarino, 2018). In the muscle stem cell niche, WNT signalling is key in coordinating MuSC transitions from quiescence, proliferation, commitment, and differentiation (Brack et al, 2008; Eliazer et al, 2019; Lacour et al, 2017; Le Grand et al, 2009; Parisi et al, 2015; Rudolf et al, 2016) Because of this central role, the WNT pathway is supervised by several mechanisms and different works have shown that lncRNAs can modulate it at both transcriptional and post-transcriptional levels (Zarkou et al, 2018). Our data show that Lnc-Rewind expression is necessary to maintain Wnt7b repressed and to allow MuSC expansion and proper differentiation
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