Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Genome wide mapping for TF binding sites for Pol II, JunD, cFos, Max & cMyc in GM12878 (ENCODE Project)

ABSTRACT: We performed ChIP-Seq for 5 different transcription factors (Pol II, JunD, cFos, Max and cMyc) as part of the ENCODE project in order to determine sites of allele-specific binding. This was done in the GM12878 cell line which was genotyped as part of the pilot II phase of the 1000 genomes project. There is a matching RNA-Seq experiemnt performed on the same cell line. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf Mapping TF binding sites for 5 different TFs to assess allele-specific binding

ORGANISM(S): Homo sapiens

SUBMITTER: Joel Rozowsky

PROVIDER: E-GEOD-30399 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

AlleleSeq: analysis of allele-specific expression and binding in a network framework.

Rozowsky Joel J Abyzov Alexej A Wang Jing J Alves Pedro P Raha Debasish D Harmanci Arif A Leng Jing J Bjornson Robert R Kong Yong Y Kitabayashi Naoki N Bhardwaj Nitin N Rubin Mark M Snyder Michael M Gerstein Mark M

Molecular systems biology 20110802

To study allele-specific expression (ASE) and binding (ASB), that is, differences between the maternally and paternally derived alleles, we have developed a computational pipeline (AlleleSeq). Our pipeline initially constructs a diploid personal genome sequence (and corresponding personalized gene annotation) using genomic sequence variants (SNPs, indels, and structural variants), and then identifies allele-specific events with significant differences in the number of mapped reads between matern ...[more]

PMID: 21811232

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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

Genome wide mapping for TF binding sites for Pol II, JunD, cFos, Max & cMyc in GM12878 (ENCODE Project)

Publications

AlleleSeq: analysis of allele-specific expression and binding in a network framework.

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