Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy
Identifieur interne : 002749 ( Main/Exploration ); précédent : 002748; suivant : 002750Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy
Auteurs : Hongqing Du [États-Unis] ; Melissa S. Cline [États-Unis] ; Robert J. Osborne [États-Unis] ; Daniel L. Tuttle [États-Unis] ; Tyson A. Clark [États-Unis] ; John Paul Donohue [États-Unis] ; Megan P. Hall [États-Unis] ; Lily Shiue [États-Unis] ; Maurice S. Swanson [États-Unis] ; Charles A. Thornton [États-Unis] ; Manuel Aresjr [États-Unis]Source :
- Nature Structural & Molecular Biology [ 1545-9993 ] ; 2010-02.
Abstract
The common form of myotonic dystrophy (DM1) is associated with the expression of expanded CTG DNA repeats as RNA (CUGexp RNA). To test whether CUGexp RNA creates a global splicing defect, we compared the skeletal muscle of two mouse models of DM1, one expressing a CTGexp transgene and another homozygous for a defective muscleblind 1 (Mbnl1) gene. Strong correlation in splicing changes for ∼100 new Mbnl1-regulated exons indicates that loss of Mbnl1 explains >80% of the splicing pathology due to CUGexp RNA. In contrast, only about half of mRNA-level changes can be attributed to loss of Mbnl1, indicating that CUGexp RNA has Mbnl1-independent effects, particularly on mRNAs for extracellular matrix proteins. We propose that CUGexp RNA causes two separate effects: loss of Mbnl1 function (disrupting splicing) and loss of another function that disrupts extracellular matrix mRNA regulation, possibly mediated by Mbnl2. These findings reveal unanticipated similarities between DM1 and other muscular dystrophies.
Myotonic dystrophy is a CUG repeat expansion disease and mice deficient in MBNL1, an RNA binding protein, show many characteristics of the disease. Comparison of gene expression profiles of two mouse models of the disease reveals that CUG repeat expansions have two effects – loss of Mbnl1 function that leads to altered splicing and loss of an as yet unknown function that disrupts extracellular matrix protein mRNA regulation.
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DOI: 10.1038/nsmb.1720
Affiliations:
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To test whether CUGexp RNA creates a global splicing defect, we compared the skeletal muscle of two mouse models of DM1, one expressing a CTGexp transgene and another homozygous for a defective muscleblind 1 (Mbnl1) gene. Strong correlation in splicing changes for ∼100 new Mbnl1-regulated exons indicates that loss of Mbnl1 explains >80% of the splicing pathology due to CUGexp RNA. In contrast, only about half of mRNA-level changes can be attributed to loss of Mbnl1, indicating that CUGexp RNA has Mbnl1-independent effects, particularly on mRNAs for extracellular matrix proteins. We propose that CUGexp RNA causes two separate effects: loss of Mbnl1 function (disrupting splicing) and loss of another function that disrupts extracellular matrix mRNA regulation, possibly mediated by Mbnl2. These findings reveal unanticipated similarities between DM1 and other muscular dystrophies.</div><div type="abstract" xml:lang="eng">Myotonic dystrophy is a CUG repeat expansion disease and mice deficient in MBNL1, an RNA binding protein, show many characteristics of the disease. Comparison of gene expression profiles of two mouse models of the disease reveals that CUG repeat expansions have two effects – loss of Mbnl1 function that leads to altered splicing and loss of an as yet unknown function that disrupts extracellular matrix protein mRNA regulation.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Californie</li><li>Floride</li><li>État de New York</li></region></list><tree><country name="États-Unis"><region name="Californie"><name sortKey="Du, Hongqing" sort="Du, Hongqing" uniqKey="Du H" first="Hongqing" last="Du">Hongqing Du</name></region><name sortKey="Aresjr, Manuel" sort="Aresjr, Manuel" uniqKey="Aresjr M" first="Manuel" last="Aresjr">Manuel Aresjr</name><name sortKey="Aresjr, Manuel" sort="Aresjr, Manuel" uniqKey="Aresjr M" first="Manuel" last="Aresjr">Manuel Aresjr</name><name sortKey="Clark, Tyson A" sort="Clark, Tyson A" uniqKey="Clark T" first="Tyson A" last="Clark">Tyson A. Clark</name><name sortKey="Cline, Melissa S" sort="Cline, Melissa S" uniqKey="Cline M" first="Melissa S" last="Cline">Melissa S. Cline</name><name sortKey="Donohue, John Paul" sort="Donohue, John Paul" uniqKey="Donohue J" first="John Paul" last="Donohue">John Paul Donohue</name><name sortKey="Hall, Megan P" sort="Hall, Megan P" uniqKey="Hall M" first="Megan P" last="Hall">Megan P. Hall</name><name sortKey="Osborne, Robert J" sort="Osborne, Robert J" uniqKey="Osborne R" first="Robert J" last="Osborne">Robert J. Osborne</name><name sortKey="Shiue, Lily" sort="Shiue, Lily" uniqKey="Shiue L" first="Lily" last="Shiue">Lily Shiue</name><name sortKey="Swanson, Maurice S" sort="Swanson, Maurice S" uniqKey="Swanson M" first="Maurice S" last="Swanson">Maurice S. Swanson</name><name sortKey="Thornton, Charles A" sort="Thornton, Charles A" uniqKey="Thornton C" first="Charles A" last="Thornton">Charles A. Thornton</name><name sortKey="Tuttle, Daniel L" sort="Tuttle, Daniel L" uniqKey="Tuttle D" first="Daniel L" last="Tuttle">Daniel L. Tuttle</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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