seRNA PAM controls skeletal muscle satellite cell proliferation and aging through trans regulation of Timp2 expression synergistically with Ddx5.

Muscle satellite cells (SCs) are responsible for muscle homeostasis and regeneration and lncRNAs play important roles in regulating SC activities. Here, in this study, we identify PAM (Pax7 Associated Muscle lncRNA) that is induced in activated/proliferating SCs upon injury to promote SC proliferation as myoblast cells. PAM is generated from a myoblast‐specific super‐enhancer (SE); as a seRNA it binds with a number of target genomic loci predominantly in trans. Further studies demonstrate that it interacts with Ddx5 to tether PAM SE to its inter‐chromosomal targets Timp2 and Vim to activate the gene expression. Lastly, we show that PAM expression is increased in aging SCs, which leads to enhanced inter‐chromosomal interaction and target genes upregulation. Altogether, our findings identify PAM as a previously unknown lncRNA that regulates both SC proliferation and aging through its trans gene regulatory activity. Muscle satellite cells (SCs) are indispensable for muscle regeneration and lncRNAs play important roles in regulating SC activities. Here, we characterize the function of lncRNA PAM in SC. We show that PAM promotes SCs proliferation by binding with Ddx5 to facilitate the chromatin interaction between PAM residing super enhancer (SE) and target loci, Timp2 and Vim. In aging mice, the activity of PAM SE is elevated to enhance the transcription of Timp2, which potentially modulates extracellular matrix (ECM) components in aging muscle.

肌肉卫星细胞（SCs）负责肌肉内稳态和再生，长链非编码RNA（lncRNAs）在调节卫星细胞活动中起重要作用。在本研究中，我们鉴定出PAM（Pax7相关肌肉长链非编码RNA），它在损伤后在活化/增殖的卫星细胞中被诱导，以促进卫星细胞作为成肌细胞增殖。PAM由成肌细胞特异性超级增强子（SE）产生；作为一种超级增强子相关RNA（seRNA），它主要以反式作用方式与许多靶基因组位点结合。进一步的研究表明，它与Ddx5相互作用，将PAM超级增强子连接到其染色体间的靶标Timp2和Vim上，以激活基因表达。最后，我们表明PAM在衰老的卫星细胞中表达增加，这导致染色体间相互作用增强以及靶基因上调。总之，我们的研究结果确定PAM是一种此前未知的长链非编码RNA，它通过其反式基因调控活性调节卫星细胞增殖和衰老。 肌肉卫星细胞（SCs）对肌肉再生不可或缺，长链非编码RNA（lncRNAs）在调节卫星细胞活动中起重要作用。在此，我们描述了长链非编码RNA PAM在卫星细胞中的功能。我们表明PAM通过与Ddx5结合，促进PAM所在的超级增强子（SE）与靶位点Timp2和Vim之间的染色质相互作用，从而促进卫星细胞增殖。在衰老小鼠中，PAM超级增强子的活性升高，以增强Timp2的转录，这可能调节衰老肌肉中的细胞外基质（ECM）成分。