Sato Michio, Kadomatsu Tsuyoshi, Miyata Keishi, Warren Junco S, Tian Zhe, Zhu Shunshun, Horiguchi Haruki, Makaju Aman, Bakhtina Anna, Morinaga Jun, Sugizaki Taichi, Hirashima Kaname, Yoshinobu Kumiko, Imasaka Mai, Araki Masatake, Komohara Yoshihiro, Wakayama Tomohiko, Nakagawa Shinichi, Franklin Sarah, Node Koichi, Araki Kimi, Oike Yuichi
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Department of Cardiovascular Medicine, School of Medicine, Saga University, Saga, Japan.
Nat Commun. 2021 May 5;12(1):2529. doi: 10.1038/s41467-021-22735-7.
In the past decade, many long noncoding RNAs (lncRNAs) have been identified and their in vitro functions defined, although in some cases their functions in vivo remain less clear. Moreover, unlike nuclear lncRNAs, the roles of cytoplasmic lncRNAs are less defined. Here, using a gene trapping approach in mouse embryonic stem cells, we identify Caren (short for cardiomyocyte-enriched noncoding transcript), a cytoplasmic lncRNA abundantly expressed in cardiomyocytes. Caren maintains cardiac function under pathological stress by inactivating the ataxia telangiectasia mutated (ATM)-DNA damage response (DDR) pathway and activating mitochondrial bioenergetics. The presence of Caren transcripts does not alter expression of nearby (cis) genes but rather decreases translation of an mRNA transcribed from a distant gene encoding histidine triad nucleotide-binding protein 1 (Hint1), which activates the ATM-DDR pathway and reduces mitochondrial respiratory capacity in cardiomyocytes. Therefore, the cytoplasmic lncRNA Caren functions in cardioprotection by regulating translation of a distant gene and maintaining cardiomyocyte homeostasis.
在过去十年间，许多长链非编码RNA（lncRNA）已被鉴定出来，其体外功能也已明确，尽管在某些情况下它们在体内的功能仍不太清楚。此外，与核lncRNA不同，细胞质lncRNA的作用还不太明确。在此，我们利用小鼠胚胎干细胞中的基因捕获方法，鉴定出了Caren（心肌细胞富集非编码转录本的简称），这是一种在心肌细胞中大量表达的细胞质lncRNA。Caren通过使共济失调毛细血管扩张症突变基因（ATM）-DNA损伤反应（DDR）通路失活并激活线粒体生物能量学，在病理应激下维持心脏功能。Caren转录本的存在不会改变附近（顺式）基因的表达，而是会减少从一个远距离基因转录而来的mRNA的翻译，该远距离基因编码组氨酸三联体核苷酸结合蛋白1（Hint1），Hint1会激活ATM-DDR通路并降低心肌细胞中的线粒体呼吸能力。因此，细胞质lncRNA Caren通过调节远距离基因的翻译和维持心肌细胞内稳态发挥心脏保护作用。
