细胞生物学
生物
再生(生物学)
RNA结合蛋白
核糖核酸
遗传学
基因
作者
Wei Fu,Hongmei Ren,Jialing Shou,Qinyu Liao,Liangpeng Li,Yu Shi,Pedro A. José,Chunyu Zeng,Wei Eric Wang
标识
DOI:10.1007/s00395-022-00921-y
摘要
The role of long non-coding RNA (lncRNA) in endogenous cardiac regeneration remains largely elusive. The mammalian cardiomyocyte is capable of regeneration for a brief period after birth. This fact allows the exploration of the roles of critical lncRNAs in the regulation of cardiac regeneration. Through a cardiac regeneration model by apical resection (AR) of the left ventricle in neonatal mice, we identified an lncRNA named natriuretic peptide A antisense RNA 1 (NPPA-AS1), which negatively regulated cardiomyocyte proliferation. In neonates, NPPA-AS1 deletion did not affect heart development, but was sufficient to prolong the postnatal window of regeneration after AR. In adult mice, NPPA-AS1 deletion improved cardiac function and reduced infarct size after myocardial infarction (MI), associated with a significant improvement in cardiomyocyte proliferation. Further analysis showed that NPPA-AS1 interacted with DNA repair-related molecule splicing factor, proline- and glutamine-rich (SFPQ). A heteromer of SFPQ and non-POU domain-containing octamer-binding protein (NONO) was required for double-strand DNA break repair, but NPPA-AS1 was competitively bound with SFPQ due to the overlapped binding sites of SFPQ and NONO. NPPA-AS1 deletion promoted the binding of SFPQ–NONO heteromer, decreased DNA damage, and activated cardiomyocyte cell cycle re-entry. Together, loss of NPPA-AS1 promoted cardiomyocyte proliferation by stabilizing SFPQ–NONO heteromer-induced DNA repair and exerted a therapeutic effect against MI in adult mice. Consequently, NPPA-AS1 may be a novel target for stimulating cardiac regeneration to treat MI.
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