Li Zheng, Cao Changchang, Zhao Quanyi, Li Dandan, Han Yan, Zhang Mingzhi, Mao Lin, Zhou Bingying, Wang Li
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China; Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences-Shenzhen, Shenzhen 518057, China.
Dev Cell. 2025 Jan 20;60(2):236-252.e8. doi: 10.1016/j.devcel.2024.09.018. Epub 2024 Oct 14.
Postnatal cardiac development requires the orchestrated maturation of diverse cellular components for which unifying control mechanisms are still lacking. Using full-length sequencing, we examined the transcriptomic landscape of the maturating mouse heart (E18.5-P28) at single-cell and transcript isoform resolution. We identified dynamically changing intercellular networks as a molecular basis of the maturing heart and alternative splicing (AS) as a common mechanism that distinguished developmental age. Manipulation of RNA-binding proteins (RBPs) remodeled the AS landscape, cardiac cell maturation, and intercellular communication through direct binding of splice targets, which were enriched for functions related to general, as well as cell-type-specific, maturation. Overexpression of an RBP nuclear cap-binding protein subunit 2 (NCBP2) in neonatal hearts repressed cardiac maturation. Together, our data suggest AS regulation by RBPs as an organ-level control mechanism in mammalian postnatal cardiac development and provide insight into the possibility of manipulating RBPs for therapeutic purposes.
出生后心脏发育需要多种细胞成分协调成熟，而目前仍缺乏统一的控制机制。我们使用全长测序技术，在单细胞和转录本异构体分辨率水平上研究了成熟小鼠心脏（胚胎期18.5天至出生后28天）的转录组图谱。我们确定了动态变化的细胞间网络是成熟心脏的分子基础，可变剪接（AS）是区分发育年龄的常见机制。操纵RNA结合蛋白（RBP）通过直接结合剪接靶点重塑了AS图谱、心脏细胞成熟和细胞间通讯，这些靶点富含与一般以及细胞类型特异性成熟相关的功能。在新生小鼠心脏中过表达RBP核帽结合蛋白亚基2（NCBP2）会抑制心脏成熟。总之，我们的数据表明RBP对AS的调控是哺乳动物出生后心脏发育中的一种器官水平控制机制，并为操纵RBP用于治疗目的的可能性提供了见解。
