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

Michio Sato,Sarah Franklin,Jason G Warren ,Shunshun Zhu,Masatake Araki,Jun Morinaga,Taichi Sugizaki,Anna Bakhtina,Mai Imasaka,Haruki Horiguchi,Aman Makaju,Shinichi Nakagawa,Yoshihiro Komohara,Koichi Node,Zhe Tian,Kimi Araki,Tsuyoshi Kadomatsu,Kaname Hirashima,Kumiko Yoshinobu,Tomohiko Wakayama,Keishi Miyata,Yuichi Oike

doi:10.1038/s41467-021-22735-7

Michio Sato, Sarah Franklin + Show 20 more

Open Access

https://doi.org/10.1038/s41467-021-22735-7

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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.

Highlights

In the past decade, many long noncoding RNAs have been identified and their in vitro functions defined, in some cases their functions in vivo remain less clear
Cardiomyocyte-enriched transcript (Caren) overexpression blocked the upregulation of histidine triad nucleotide-binding protein 1 (Hint1), which activates ataxia telangiectasia mutated (ATM) serine/threonine kinase, a DNA damage response (DDR) regulator closely linked to heart failure (HF) development and progression[17,20]
Here we used a gene trapping approach and identified Caren as a cytoplasmic IncRNA that protects against the development of cardiac hypertrophy and failure under pressure overload

Summary

Introduction

Many long noncoding RNAs (lncRNAs) have been identified and their in vitro functions defined, in some cases their functions in vivo remain less clear. Caren maintains cardiac function under pathological stress by inactivating the ataxia telangiectasia mutated (ATM)-DNA damage response (DDR) pathway and activating mitochondrial bioenergetics. Sequence-tagged insertional mutations and can be coupled to expression and/or function-based assays We have applied this approach to identify and characterize functional cytoplasmic lncRNAs. DNA damage and subsequent activation of the DNA damage response (DDR) occurs in cardiomyocytes of heart failure (HF) patients[13,14,15]. Caren overexpression blocked the upregulation of histidine triad nucleotide-binding protein 1 (Hint1), which activates ataxia telangiectasia mutated (ATM) serine/threonine kinase, a DNA damage response (DDR) regulator closely linked to HF development and progression[17,20]. We identify a cytoplasmic lncRNA that counteracts HF development by inactivating the ATM-DDR pathway and activating mitochondrial bioenergetics by regulating the translation of a distant (trans) gene

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