The lncRNA Caren antagonizes heart failure by inactivating DNA damage response and activating mitochondrial biogenesis.
Michio SatoTsuyoshi KadomatsuKeishi MiyataJunco S WarrenZhe TianShunshun ZhuHaruki HoriguchiAman MakajuAnna A BakhtinaJun MorinagaTaichi SugizakiKaname HirashimaKumiko YoshinobuMai ImasakaMasatake ArakiYoshihiro KomoharaTomohiko WakayamaShinichi NakagawaSarah FranklinKoichi NodeKimi ArakiYuichi OikePublished in: Nature communications (2021)
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.
Keyphrases
- dna damage response
- genome wide identification
- genome wide analysis
- binding protein
- dna repair
- genome wide
- oxidative stress
- heart failure
- transcription factor
- copy number
- embryonic stem cells
- long non coding rna
- signaling pathway
- high glucose
- long noncoding rna
- lymph node
- poor prognosis
- dna damage
- angiotensin ii
- network analysis
- gene expression
- dna methylation
- endothelial cells
- heat stress
- wild type