Extensive alternative splicing transitions during postnatal skeletal muscle development are required for calcium handling functions
Extensive alternative splicing transitions during postnatal skeletal muscle development are required for calcium handling functions
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DOI：
10.7554/elife.27192
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发表时间：
2017-08-11
期刊：
影响因子：
7.7
通讯作者：
Cooper, Thomas A.
中科院分区：
文献类型：
--
作者：
Brinegar, Amy E.;Xia, Zheng;Cooper, Thomas A.
骨骼肌的出生后发育是组织重塑的高度动态时期。在这里，我们使用 RNA-seq 来识别从胚胎晚期到成年小鼠肌肉的转录组变化，并证明选择性剪接发育转变影响肌肉生理学。出生后的前两周对于差异基因表达和选择性剪接转变尤其活跃，并且在经历选择性剪接的基因中，钙处理功能显着丰富。我们重点关注三个钙调神经磷酸酶 A 基因（调节肌肉生物学多个方面的钙依赖性磷酸酶）的出生后剪接转变。钙调神经磷酸酶 A 与成人肌肉和分化的 C2C12 中胎儿亚型的重定向剪接会减慢肌肉松弛的时间，促进钙调神经磷酸酶靶标 Nfatc3 的核定位，和/或影响 Nfatc 转录靶标的表达。结果证明了钙调神经磷酸酶亚型以前未知的特异性以及选择性剪接在肌肉产后发育过程中的更广泛影响。
Postnatal development of skeletal muscle is a highly dynamic period of tissue remodeling. Here, we used RNA-seq to identify transcriptome changes from late embryonic to adult mouse muscle and demonstrate that alternative splicing developmental transitions impact muscle physiology. The first 2 weeks after birth are particularly dynamic for differential gene expression and alternative splicing transitions, and calcium-handling functions are significantly enriched among genes that undergo alternative splicing. We focused on the postnatal splicing transitions of the three calcineurin A genes, calcium-dependent phosphatases that regulate multiple aspects of muscle biology. Redirected splicing of calcineurin A to the fetal isoforms in adult muscle and in differentiated C2C12 slows the timing of muscle relaxation, promotes nuclear localization of calcineurin target Nfatc3, and/or affects expression of Nfatc transcription targets. The results demonstrate a previously unknown specificity of calcineurin isoforms as well as the broader impact of alternative splicing during muscle postnatal development.