Antagonistic regulation of mRNA expression and splicing by CELF and MBNL proteins.
Antagonistic regulation of mRNA expression and splicing by CELF and MBNL proteins.
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DOI：
10.1101/gr.184390.114
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发表时间：
2015-06
期刊：
影响因子：
7
通讯作者：
Burge CB
中科院分区：
文献类型：
--
作者：
Wang ET;Ward AJ;Cherone JM;Giudice J;Wang TT;Treacy DJ;Lambert NJ;Freese P;Saxena T;Cooper TA;Burge CB
保守的 CUGBP1、Elav 样因子 (CELF) 家族的 RNA 结合蛋白有助于心脏和骨骼肌的发育，并与强直性肌营养不良 (DM) 有关。为了了解它们的全基因组功能，我们通过 RNA-seq 分析了成年小鼠心脏中 CELF1 或 CELF2 以及肌肉中 CELF1 诱导后的转录组动态，并辅以小鼠细胞和组织的交联/免疫沉淀测序 (CLIP-seq) 分析，以区分直接和间接调控靶点。我们发现了数百个 mRNA 被 CELF1 和发育诱导的 MBNL1 蛋白结合在其 3' UTR 中，目标信息的重叠比预期多三倍，包括涉及发育和细胞分化的信息。 CELF1 和 MBNL1 的 3' UTR 结合程度分别预测了 CELF1 诱导后 mRNA 抑制或稳定的程度。然而，CELF1 的 RNA 体外结合特异性并未因与重组 MBNL1 共孵育而发生明显改变。这些发现支持这样一个模型：CELF 和 MBNL 蛋白独立地与 mRNA 结合，但在功能上竞争，分别指定数百个 mRNA 靶标的下调或定位/稳定。许多替代 3' UTR 亚型的表达在 CELF1 诱导后发生改变，3' UTR 结合与亚型和基因的下调相关。数百个替代外显子的剪接受到这些蛋白质的相反调节，证实了先前在少数病例中观察到的额外一层调节拮抗作用。 CELF 和 MBNL 之间控制 mRNA 丰度和剪接的调节关系似乎已经进化，以增强心脏和肌肉基因主要类别的发育转变。
RNA binding proteins of the conserved CUGBP1, Elav-like factor (CELF) family contribute to heart and skeletal muscle development and are implicated in myotonic dystrophy (DM). To understand their genome-wide functions, we analyzed the transcriptome dynamics following induction of CELF1 or CELF2 in adult mouse heart and of CELF1 in muscle by RNA-seq, complemented by crosslinking/immunoprecipitation-sequencing (CLIP-seq) analysis of mouse cells and tissues to distinguish direct from indirect regulatory targets. We identified hundreds of mRNAs bound in their 3′ UTRs by both CELF1 and the developmentally induced MBNL1 protein, a threefold greater overlap in target messages than expected, including messages involved in development and cell differentiation. The extent of 3′ UTR binding by CELF1 and MBNL1 predicted the degree of mRNA repression or stabilization, respectively, following CELF1 induction. However, CELF1's RNA binding specificity in vitro was not detectably altered by coincubation with recombinant MBNL1. These findings support a model in which CELF and MBNL proteins bind independently to mRNAs but functionally compete to specify down-regulation or localization/stabilization, respectively, of hundreds of mRNA targets. Expression of many alternative 3′ UTR isoforms was altered following CELF1 induction, with 3′ UTR binding associated with down-regulation of isoforms and genes. The splicing of hundreds of alternative exons was oppositely regulated by these proteins, confirming an additional layer of regulatory antagonism previously observed in a handful of cases. The regulatory relationships between CELFs and MBNLs in control of both mRNA abundance and splicing appear to have evolved to enhance developmental transitions in major classes of heart and muscle genes.
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影响因子：
14.9
作者：
Goo YH;Cooper TA
通讯作者：
Cooper TA
DOI：
10.1016/j.mcn.2012.12.003
发表时间：
2013-09
期刊：
Molecular and cellular neurosciences
影响因子：
--
作者：
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通讯作者：
Ladd AN
影响因子：
48
作者：
Katz, Yarden;Wang, Eric T.;Airoldi, Edoardo M.;Burge, Christopher B.
通讯作者：
Burge, Christopher B.
DOI：
10.1073/pnas.0900028106
发表时间：
2009-04-28
影响因子：
11.1
作者：
Ji, Zhe;Lee, Ju Youn;Tian, Bin
通讯作者：
Tian, Bin
影响因子：
4
作者：
Ho, TH;Savkur, RS;Cooper, TA
通讯作者：
Cooper, TA