Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression data from DM1, DM2 and Normal Adult Skeletal Muscle Biopsies

ABSTRACT: DM1 and DM2 biopsies from patients were compared to Normal adult individuals Keywords: 3 groups of samples 10 DM1 biopsies, 20 DM2 biopsies, and 6 Normal individuals biopsies

ORGANISM(S): Homo sapiens

SUBMITTER: Mario Sirito

PROVIDER: E-GEOD-7014 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Differences in aberrant expression and splicing of sarcomeric proteins in the myotonic dystrophies DM1 and DM2.

Vihola Anna A Bachinski Linda L LL Sirito Mario M Olufemi Shodimu-Emmanuel SE Hajibashi Shohrae S Baggerly Keith A KA Raheem Olayinka O Haapasalo Hannu H Suominen Tiina T Holmlund-Hampf Jeanette J Paetau Anders A Cardani Rosanna R Meola Giovanni G Kalimo Hannu H Edström Lars L Krahe Ralf R Udd Bjarne B

Acta neuropathologica 20100112 4

Aberrant transcription and mRNA processing of multiple genes due to RNA-mediated toxic gain-of-function has been suggested to cause the complex phenotype in myotonic dystrophies type 1 and 2 (DM1 and DM2). However, the molecular basis of muscle weakness and wasting and the different pattern of muscle involvement in DM1 and DM2 are not well understood. We have analyzed the mRNA expression of genes encoding muscle-specific proteins and transcription factors by microarray profiling and studied sele ...[more]

PMID: 20066428

Publication: 1/2

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Project description:For some neurological disorders, disease is primarily RNA-mediated due to expression of non-coding microsatellite expansion RNAs (RNAexp). Toxicity is thought to result from enhanced binding of proteins to these expansions and depletion from their normal cellular targets. However, experimental evidence for this sequestration model is lacking. Here, we use HITS-CLIP and pre-mRNA processing analysis of human control versus myotonic dystrophy (DM) brains to provide compelling evidence for this RNA toxicity model. MBNL2 binds directly to DM repeat expansions in the brain resulting in depletion from its normal RNA targets with downstream effects on alternative splicing and polyadenylation. Similar RNA processing defects were detected in Mbnl compound knockout mice, highlighted by dysregulation of Mapt splicing and fetal tau isoform expression in adults. These results demonstrate that MBNL proteins are directly sequestered by RNAexp in the DM brain and introduce a powerful experimental tool to evaluate RNA-mediated toxicity in other expansion diseases. HITS-CLIP analysis was performed to identify RNA binding sites of MBNL2 in control, DM type 1 (DM1), and DM type 2 (DM2) autopsy-derived brain (n=3). Two regions of the brain selected for the study included the frontal cortex and hippocampus. Libraries were sequenced and wiggle files were generated for each biological replicate as well as three pooled biological replicates (3BRs) per group (control, DM1, and DM2). In addition, differential CLIP analysis (dCLIP) was performed to normalize binding data between groups and identify statistically significant changes in binding. The dCLIP analysis generated bedgraph files representing normalized binding profiles of MBNL2 in each group (control, DM1, and DM2) for visualization and comparative analysis. PolyA-seq was performed on control, DM1, and DM2 autopsy-derived brain samples (hippocampus and frontal cortex, n=3) as well as wild-type (WT) and Mbnl1; Mbnl2 conditional double knockout (Mbnl1-/-; Mbnl2c/c; Nestin-Cre+/- or DKO) brain (n=3). Libraries were sequenced and the resultant files were processed and aligned to the reference genomes (hg19 and mm10). Further computational processing was performed to remove internal oligo(dT) mis-priming events, identify valid polyA sites, and trim to the exact polyA sites. BedGraph files were generated for each group in human (control, DM1, and DM2) and mouse (WT and Mbnl DKO) for comparative visualization.

Dataset Information

Expression data from DM1, DM2 and Normal Adult Skeletal Muscle Biopsies

Publications

Differences in aberrant expression and splicing of sarcomeric proteins in the myotonic dystrophies DM1 and DM2.

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