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Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome.

Mutations in the human MECP2 gene cause Rett syndrome (RTT), a severe neurodevelopmental disorder that predominantly affects girls. Despite decades of work, the molecular function of MeCP2 is not fully understood. Here we report a systematic identification of MeCP2-interacting proteins in the mouse... Full description

Journal Title: PLoS genetics June 2016, Vol.12(6), p.e1006129
Main Author: Li, Ronghui
Other Authors: Dong, Qiping , Yuan, Xinni , Zeng, Xin , Gao, Yu , Chiao, Cassandra , Li, Hongda , Zhao, Xinyu , Keles, Sunduz , Wang, Zefeng , Chang, Qiang
Format: Electronic Article Electronic Article
Language: English
Subjects:
RNA
ID: E-ISSN: 1553-7404 ; DOI: 1553-7404 ; DOI: 10.1371/journal.pgen.1006129
Link: http://search.proquest.com/docview/1800702560/?pq-origsite=primo
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title: Misregulation of Alternative Splicing in a Mouse Model of Rett Syndrome.
format: Article
creator:
  • Li, Ronghui
  • Dong, Qiping
  • Yuan, Xinni
  • Zeng, Xin
  • Gao, Yu
  • Chiao, Cassandra
  • Li, Hongda
  • Zhao, Xinyu
  • Keles, Sunduz
  • Wang, Zefeng
  • Chang, Qiang
subjects:
  • Alternative Splicing–Genetics
  • Animals–Metabolism
  • Brain–Genetics
  • Disease Models, Animal–Genetics
  • Exons–Genetics
  • Female–Genetics
  • Male–Genetics
  • Methyl-Cpg-Binding Protein 2–Genetics
  • Mice–Genetics
  • Mice, Knockout–Genetics
  • Mutation–Genetics
  • Phenotype–Genetics
  • RNA–Genetics
  • Rett Syndrome–Genetics
  • Methyl-Cpg-Binding Protein 2
  • RNA
ispartof: PLoS genetics, June 2016, Vol.12(6), p.e1006129
description: Mutations in the human MECP2 gene cause Rett syndrome (RTT), a severe neurodevelopmental disorder that predominantly affects girls. Despite decades of work, the molecular function of MeCP2 is not fully understood. Here we report a systematic identification of MeCP2-interacting proteins in the mouse brain. In addition to transcription regulators, we found that MeCP2 physically interacts with several modulators of RNA splicing, including LEDGF and DHX9. These interactions are disrupted by RTT causing mutations, suggesting that they may play a role in RTT pathogenesis. Consistent with the idea, deep RNA sequencing revealed misregulation of hundreds of splicing events in the cortex of Mecp2 knockout mice. To reveal the functional consequence of altered RNA splicing due to the loss of MeCP2, we focused on the regulation of the splicing of the flip/flop exon of Gria2 and other AMPAR genes. We found a significant splicing shift in the flip/flop exon toward the flop inclusion, leading to a faster decay in the AMPAR gated current and altered synaptic transmission. In summary, our study identified direct physical interaction between MeCP2 and splicing factors, a novel MeCP2 target gene, and established functional connection between a specific RNA splicing change and synaptic phenotypes in RTT mice. These results not only help our understanding of the molecular function of MeCP2, but also reveal potential drug targets for future therapies. Author Summary Rett syndrome (RTT) is a debilitating neurodevelopmental disorder with no cure or effective treatment. To fully understand the disease mechanism and develop therapies, it is necessary to study all aspects of the molecular function of methyl-CpG binding protein 2 (MeCP2), mutations in which have been identified as the genetic cause of RTT. Over the years, MeCP2 has been shown to maintain DNA methylation, regulate transcription and chromatin structure, control microRNA processing, and modulate RNA splicing. Among these known functions, the role of MeCP2 in modulating RNA splicing is less well understood. We took several unbiased approaches to investigate the how MeCP2 may regulate splicing, what splicing changes are caused by the loss of MeCP2, and what functional consequences are caused by altered splicing. We discovered that MeCP2 interacts with splicing factors to regulated the splicing of glutamate receptor genes, which mediate the vast majority of excitatory synaptic transmission in the brain; and linked the alter
language: eng
source:
identifier: E-ISSN: 1553-7404 ; DOI: 1553-7404 ; DOI: 10.1371/journal.pgen.1006129
fulltext: fulltext
issn:
  • 15537404
  • 1553-7404
url: Link


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titleMisregulation of Alternative Splicing in a Mouse Model of Rett Syndrome.
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descriptionMutations in the human MECP2 gene cause Rett syndrome (RTT), a severe neurodevelopmental disorder that predominantly affects girls. Despite decades of work, the molecular function of MeCP2 is not fully understood. Here we report a systematic identification of MeCP2-interacting proteins in the mouse brain. In addition to transcription regulators, we found that MeCP2 physically interacts with several modulators of RNA splicing, including LEDGF and DHX9. These interactions are disrupted by RTT causing mutations, suggesting that they may play a role in RTT pathogenesis. Consistent with the idea, deep RNA sequencing revealed misregulation of hundreds of splicing events in the cortex of Mecp2 knockout mice. To reveal the functional consequence of altered RNA splicing due to the loss of MeCP2, we focused on the regulation of the splicing of the flip/flop exon of Gria2 and other AMPAR genes. We found a significant splicing shift in the flip/flop exon toward the flop inclusion, leading to a faster decay in the AMPAR gated current and altered synaptic transmission. In summary, our study identified direct physical interaction between MeCP2 and splicing factors, a novel MeCP2 target gene, and established functional connection between a specific RNA splicing change and synaptic phenotypes in RTT mice. These results not only help our understanding of the molecular function of MeCP2, but also reveal potential drug targets for future therapies. Author Summary Rett syndrome (RTT) is a debilitating neurodevelopmental disorder with no cure or effective treatment. To fully understand the disease mechanism and develop therapies, it is necessary to study all aspects of the molecular function of methyl-CpG binding protein 2 (MeCP2), mutations in which have been identified as the genetic cause of RTT. Over the years, MeCP2 has been shown to maintain DNA methylation, regulate transcription and chromatin structure, control microRNA processing, and modulate RNA splicing. Among these known functions, the role of MeCP2 in modulating RNA splicing is less well understood. We took several unbiased approaches to investigate the how MeCP2 may regulate splicing, what splicing changes are caused by the loss of MeCP2, and what functional consequences are caused by altered splicing. We discovered that MeCP2 interacts with splicing factors to regulated the splicing of glutamate receptor genes, which mediate the vast majority of excitatory synaptic transmission in the brain; and linked the altered splicing of glutamate receptor genes to specific synaptic changes in a RTT mouse model. Our findings not only advance the understanding of RTT disease mechanism, but also reveal a potential drug target for future development of therapies.
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