The lncRNA Caren antagonizes heart failure by inactivating DNA damage response and activating mitochondrial biogenesis

Michio Sato, Tsuyoshi Kadomatsu, Keishi Miyata, Junco S. Warren, Zhe Tian, Shunshun Zhu, Haruki Horiguchi, Aman Makaju, Anna Bakhtina, Jun Morinaga, Taichi Sugizaki, Kaname Hirashima, Kumiko Yoshinobu, Mai Imasaka, Masatake Araki, Yoshihiro Komohara, Tomohiko Wakayama, Shinichi Nakagawa, Sarah Franklin, Koichi Node, Kimi Araki and Yuichi Oike ()
Additional contact information
Michio Sato: Kumamoto University
Tsuyoshi Kadomatsu: Kumamoto University
Keishi Miyata: Kumamoto University
Junco S. Warren: Kumamoto University
Zhe Tian: Kumamoto University
Shunshun Zhu: Kumamoto University
Haruki Horiguchi: Kumamoto University
Aman Makaju: University of Utah
Anna Bakhtina: University of Utah
Jun Morinaga: Kumamoto University
Taichi Sugizaki: Kumamoto University
Kaname Hirashima: Kumamoto University
Kumiko Yoshinobu: Kumamoto University
Mai Imasaka: Kumamoto University
Masatake Araki: Kumamoto University
Yoshihiro Komohara: Kumamoto University
Tomohiko Wakayama: Kumamoto University
Shinichi Nakagawa: Hokkaido University
Sarah Franklin: University of Utah
Koichi Node: Saga University
Kimi Araki: Kumamoto University
Yuichi Oike: Kumamoto University

Nature Communications, 2021, vol. 12, issue 1, 1-21

Abstract: Abstract 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22735-7

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DOI: 10.1038/s41467-021-22735-7

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