Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Muscleblind-Like 2 mediated alternative splicing in the developing bain by mRNA sequencing

ABSTRACT: We have identified Mbnl2 mediated splicing events and mRNA expression regulation by comparing WT and Mbnl2 ?E2/?E2 mouse hippocampii using Affymetrix Mouse Exon Junction Array and mRNA sequencing. The splicing microarray data has already been submitted under GSE37908 which also includes a re-analysis of RNA-seq data. The TableS1.xls contains Splicing microarray analysis data of Mbnl2+/+ vs. MBNL2 ?E2/?E2 knockout hippocampus. The TableS2.xls files contain RNA-Seq, Gene Ontology, HITS-CLIP and CIMS summary of Mbnl2+/+ vs. MBNL2 ?E2/?E2 knockout hippocampus. The file contents are descibed in the 'TableS1_S2_readme.pdf' and data processing details are included in the 'data_processing_readme.pdf' file. 6 total samples were analyzed: brains from 3 WT and 3 MBNL2 ?E2/?E2 female mice, all 2-3 months of age.

ORGANISM(S): Mus musculus

SUBMITTER: Ranjan Batra

PROVIDER: E-GEOD-38497 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Muscleblind-like 2-mediated alternative splicing in the developing brain and dysregulation in myotonic dystrophy.

Charizanis Konstantinos K Lee Kuang-Yung KY Batra Ranjan R Goodwin Marianne M Zhang Chaolin C Yuan Yuan Y Shiue Lily L Cline Melissa M Scotti Marina M MM Xia Guangbin G Kumar Ashok A Ashizawa Tetsuo T Clark H Brent HB Kimura Takashi T Takahashi Masanori P MP Fujimura Harutoshi H Jinnai Kenji K Yoshikawa Hiroo H Gomes-Pereira Mário M Gourdon Geneviève G Sakai Noriaki N Nishino Seiji S Foster Thomas C TC Ares Manuel M Darnell Robert B RB Swanson Maurice S MS

Neuron 20120801 3

The RNA-mediated disease model for myotonic dystrophy (DM) proposes that microsatellite C(C)TG expansions express toxic RNAs that disrupt splicing regulation by altering MBNL1 and CELF1 activities. While this model explains DM manifestations in muscle, less is known about the effects of C(C)UG expression on the brain. Here, we report that Mbnl2 knockout mice develop several DM-associated central nervous system (CNS) features including abnormal REM sleep propensity and deficits in spatial memory. ...[more]

PMID: 22884328

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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

Muscleblind-Like 2 mediated alternative splicing in the developing bain by mRNA sequencing

Publications

Muscleblind-like 2-mediated alternative splicing in the developing brain and dysregulation in myotonic dystrophy.

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