可变剪接在肌肉发育中的作用研究进展

Research Progress on the Role of Alternative Splicing in Muscle Development

可变剪接发生在DNA转录为前体mRNA后,通过该过程可以使单个基因产生多个mRNA异构体和蛋白质亚型,增加了转录后加工过程中基因的信息多样性和蛋白质丰度。剪接体、剪接因子和其他RNA结合蛋白催化识别剪接位点和可变剪接外显子,参与调节可变剪接,从进化的角度来看,可变剪接在一定程度上为生物进化提供了驱动力。可变剪接作为组织特异性调节剂,参与肌肉发育的整个过程。在成肌细胞分化过程中,多聚嘧啶序列结合蛋白(polypyrimidine tract-binding protein,PTB)和RNA结合蛋白4(RNA-binding motif protein 4,RBM4)分别与原肌球蛋白的内含子多嘧啶序列和富含CU的内含子结合,共同调节α-原肌球蛋白的肌肉细胞特异性外显子选择的活性。RBM4可通过下调PTB表达并颉颃PTB在外显子选择中的活性来协同作用于肌细胞增殖分化的特异性剪接;肌球蛋白Ⅰ亚型通过可变剪接产生4种不同长度杠杆臂的蛋白质,影响肌肉的张力与拉伸激活;可变剪接可能是产生肌肉类型特异性的重要机制,选择性剪接产生具有不同催化动力学的肌球蛋白重链同工型,催化动力学差异地调节收缩性,从而影响肌纤维类型和肌肉功能。作者通过阐述可变剪接事件在肌肉发育及肌纤维形成过程中的主要作用,揭示可变剪接对肌肉发育的作用,以期为后续研究肌肉的发育调控机理提供参考依据。

Alternative splicing occurs after DNA is transcribed into precursor mRNA,and multiple mRNA isomers and protein subtypes can be produced from a single gene through this process,which increases the information diversity and protein abundance of genes during post-transcriptional processing.Spliceosomes,splicing factors and other RNA-binding proteins catalyse the recognition of splicing sites and alternative splicing exons,and participate in the regulation of alternative splicing.From the perspective of evolution,alternative splicing provides a driving force for biological evolution to some extent.As a tissue-specific regulator,alternative splicing is involved in the whole process of muscle development.During myoblast differentiation,polypyrimidine tract-binding protein(PTB)and RNA-binding motif protein 4(RNA-binding motif protein 4,RBM4)binds to the intron polypyrimidine sequence of tropomyosin and the CU-rich intron,respectively,and modulate the activity of muscle cell-specific exon selection of alpha-tropomyosin.RBM4 plays a synergistic role in the specific splicing of muscle cell proliferation and differentiation by down-regulating the expression of PTB and antagonizing the activity of PTB exon selection.MyosinⅠsubtype produces proteins of four different length lever arms through alternative splicing,which affect muscle tension and muscle stretching activation.Alternative splicing may be an important mechanism for the generation of muscle type specificity.Selective splicing produces myosin heavy chain isoforms with different catalytic kinetics,which regulate contractiity differently,thus affecting muscle fiber type and muscle function.By expounding the main roles of alternative splicing events in muscle development and muscle fiber formation,the author revealed the role of alternative splicing on muscle development,in the hope of providing a reference for the follow-up research on muscle development regulation mechanism.