Loss of MBNL leads to disruption of developmentally regulated alternative polyadenylation in RNA-mediated disease.
Loss of MBNL leads to disruption of developmentally regulated alternative polyadenylation in RNA-mediated disease.
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DOI：
10.1016/j.molcel.2014.08.027
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发表时间：
2014-10-23
期刊：
影响因子：
16
通讯作者：
Swanson, Maurice S.
中科院分区：
文献类型：
--
作者：
Batra, Ranjan;Charizanis, Konstantinos;Manchanda, Mini;Mohan, Apoorva;Li, Moyi;Finn, Dustin J.;Goodwin, Marianne;Zhang, Chaolin;Sobczak, Krzysztof;Thornton, Charles A.;Swanson, Maurice S.
由于微卫星扩增RNA的隔离而抑制肌盲样（MBNL）活性是RNA介导的强直性肌营养不良（DM）疾病中的主要致病事件。虽然MBNL 1和MBNL 2与新生转录物结合以调节肌肉和大脑发育期间的选择性剪接，但MBNL蛋白家族的另一个主要结合位点是靶RNA的3′非翻译区。在这里，我们报告了小鼠胚胎成纤维细胞中Mbnl蛋白的耗尽导致数千种替代聚腺苷酸化事件的错误调节。HITS-CLIP和小基因报告分析表明，这些多聚腺苷酸化开关是MBNL结合靶RNA的直接结果。在小鼠polyCUG模型和人DM的骨骼肌中也发生了错误调节的替代性多聚腺苷酸化，导致新生儿多聚腺苷酸化模式持续存在。这些发现揭示了MBNL蛋白质的新的发育功能，并证明DM的特征在于在多个水平上对前mRNA加工的错误调节。
Inhibition of muscleblind-like (MBNL) activity due to sequestration by microsatellite expansion RNAs is a major pathogenic event in the RNA-mediated disease myotonic dystrophy (DM). Although MBNL1 and MBNL2 bind to nascent transcripts to regulate alternative splicing during muscle and brain development, another major binding site for the MBNL protein family is the 3′ untranslated region of target RNAs. Here, we report that depletion of Mbnl proteins in mouse embryo fibroblasts leads to mis-regulation of thousands of alternative polyadenylation events. HITS-CLIP and minigene reporter analyses indicate that these polyadenylation switches are a direct consequence of MBNL binding to target RNAs. Mis-regulated alternative polyadenylation also occurs in skeletal muscle in a mouse polyCUG model and human DM resulting in the persistence of neonatal polyadenylation patterns. These findings reveal a novel developmental function for MBNL proteins and demonstrate that DM is characterized by mis-regulation of pre-mRNA processing at multiple levels.
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影响因子：
11.1
作者：
Lee, Kuang-Yung;Li, Moyi;Manchanda, Mini;Batra, Ranjan;Charizanis, Konstantinos;Mohan, Apoorva;Warren, Sonisha A.;Chamberlain, Christopher M.;Finn, Dustin;Hong, Hannah;Ashraf, Hassan;Kasahara, Hideko;Ranum, Laura P. W.;Swanson, Maurice S.
通讯作者：
Swanson, Maurice S.
影响因子：
4.8
作者：
Cohen, Todd J.;Waddell, David S.;Yao, Tso-Pang
通讯作者：
Yao, Tso-Pang
影响因子：
3.5
作者：
Chamberlain, Christopher M.;Ranum, Laura P. W.
通讯作者：
Ranum, Laura P. W.
影响因子：
11.2
作者：
Nakamori, Masayuki;Sobczak, Krzysztof;Puwanant, Araya;Welle, Steve;Eichinger, Katy;Pandya, Shree;Dekdebrun, Jeannne;Heatwole, Chad R.;McDermott, Michael P.;Chen, Tian;Cline, Melissa;Tawil, Rabi;Osborne, Robert J.;Wheeler, Thurman M.;Swanson, Maurice S.;Moxley, Richard T., III;Thornton, Charles A.
通讯作者：
Thornton, Charles A.
影响因子：
64.5
作者：
Mayr C;Bartel DP
通讯作者：
Bartel DP