Conserved functional antagonism of CELF and MBNL proteins controls stem cell-specific alternative splicing in planarians-猫眼课题宝

DOI：

10.7554/elife.16797

发表时间：

2016-08

期刊：

eLife

影响因子：

7.7

通讯作者：

中科院分区：

生物学1区

文献类型：

作者：

Jordi Solana;M. Irimia;Salah Ayoub;M. R. Orejuela;Vera Zywitza;Marvin Jens;Javier Tapial;D. Ray;Q. Morris;T. Hughes;B. Blencowe;N. Rajewsky

与转录调控相反，干细胞中选择性剪接（AS）的功能知之甚少。在哺乳动物中，MBNL 蛋白负向调节胚胎干细胞特有的外显子程序；然而，人们对这种调节的体内意义知之甚少。我们在干细胞生物学的强大体内模型——涡虫 Schmidtea mediterranea 中研究了 AS。我们发现了一个由数百个替代外显子、微外显子和内含子组成的保守 AS 程序，该程序在涡虫干细胞中受到差异性调节，并全面鉴定了其调节因子。我们发现 CELF 和 MBNL 因子之间的功能拮抗作用直接控制涡虫中干细胞特异性的 AS，将这种调节机制的起源置于两侧对称动物的基础上。 CELF 或 MBNL 因子的敲低分别通过影响基因的自我更新和分化组而导致异常的再生能力。这些结果强调了 AS 相互作用在后生动物干细胞调节中的重要性。 DOI：http://dx.doi.org/10.7554/eLife.16797.001

In contrast to transcriptional regulation, the function of alternative splicing (AS) in stem cells is poorly understood. In mammals, MBNL proteins negatively regulate an exon program specific of embryonic stem cells; however, little is known about the in vivo significance of this regulation. We studied AS in a powerful in vivo model for stem cell biology, the planarian Schmidtea mediterranea. We discover a conserved AS program comprising hundreds of alternative exons, microexons and introns that is differentially regulated in planarian stem cells, and comprehensively identify its regulators. We show that functional antagonism between CELF and MBNL factors directly controls stem cell-specific AS in planarians, placing the origin of this regulatory mechanism at the base of Bilaterians. Knockdown of CELF or MBNL factors lead to abnormal regenerative capacities by affecting self-renewal and differentiation sets of genes, respectively. These results highlight the importance of AS interactions in stem cell regulation across metazoans. DOI: http://dx.doi.org/10.7554/eLife.16797.001

Conserved functional antagonism of CELF and MBNL proteins controls stem cell-specific alternative splicing in planarians

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