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.

中文翻译：

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RNA 剪接控制小鼠出生后心脏的器官范围成熟


出生后心脏发育需要不同细胞成分的协调成熟，而这些细胞成分仍然缺乏统一的控制机制。使用全长测序，我们在单细胞和转录异构体分辨率下检查了成熟小鼠心脏 （E18.5-P28） 的转录组景观。我们确定动态变化的细胞间网络是成熟心脏的分子基础，而选择性剪接 （AS） 是区分发育年龄的常见机制。RNA 结合蛋白 （RBP） 的操纵通过剪接靶标的直接结合重塑了 AS 景观、心肌细胞成熟和细胞间通讯，这些靶标富集了与一般和细胞类型特异性成熟相关的功能。新生儿心脏中 RBP 核帽结合蛋白亚基 2 （NCBP2） 的过表达抑制了心脏成熟。总之，我们的数据表明 RBP 的 AS 调节是哺乳动物出生后心脏发育中的器官水平控制机制，并为操纵 RBP 用于治疗目的的可能性提供了见解。