Allele-specific binding of RNA-binding proteins reveals functional genetic variants in the RNA

Allele-specific protein-RNA binding is an essential aspect that may reveal functional genetic variants (GVs) mediating post-transcriptional regulation. Recently, genome-wide detection of in vivo binding of RNA-binding proteins is greatly facilitated by the enhanced crosslinking and immunoprecipitati...

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Bibliographic Details
Published in:Nature communications 2019-03, Vol.10 (1), p.1338-15, Article 1338
Main Authors: Yang, Ei-Wen, Bahn, Jae Hoon, Hsiao, Esther Yun-Hua, Tan, Boon Xin, Sun, Yiwei, Fu, Ting, Zhou, Bo, Van Nostrand, Eric L., Pratt, Gabriel A., Freese, Peter, Wei, Xintao, Quinones-Valdez, Giovanni, Urban, Alexander E., Graveley, Brenton R., Burge, Christopher B., Yeo, Gene W., Xiao, Xinshu
Format: Article
Language:English
Subjects:
3' Untranslated Regions - genetics
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38/91
45
631/114
631/208
631/208/199
Alleles
Amino Acid Motifs
Base Sequence
Binding
Computational Biology
Computer applications
Computer Simulation
Crosslinking
Data processing
Disease - genetics
Gene expression
Gene regulation
Genetic diversity
Genetic Predisposition to Disease
Genetic variance
Genetic Variation
Genomes
Hep G2 Cells
Humanities and Social Sciences
Humans
Immunoprecipitation
K562 Cells
multidisciplinary
Polymorphism, Single Nucleotide - genetics
Post-transcription
Protein Binding
Proteins
Quantitative Trait Loci - genetics
Reproducibility of Results
Ribonucleic acid
RNA
RNA - genetics
RNA Helicases - metabolism
RNA Splicing - genetics
RNA, Messenger - genetics
RNA, Messenger - metabolism
RNA-binding protein
RNA-Binding Proteins - metabolism
Science
Science (multidisciplinary)
Splicing
Trans-Activators - metabolism
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Summary:Allele-specific protein-RNA binding is an essential aspect that may reveal functional genetic variants (GVs) mediating post-transcriptional regulation. Recently, genome-wide detection of in vivo binding of RNA-binding proteins is greatly facilitated by the enhanced crosslinking and immunoprecipitation (eCLIP) method. We developed a new computational approach, called BEAPR, to identify allele-specific binding (ASB) events in eCLIP-Seq data. BEAPR takes into account crosslinking-induced sequence propensity and variations between replicated experiments. Using simulated and actual data, we show that BEAPR largely outperforms often-used count analysis methods. Importantly, BEAPR overcomes the inherent overdispersion problem of these methods. Complemented by experimental validations, we demonstrate that the application of BEAPR to ENCODE eCLIP-Seq data of 154 proteins helps to predict functional GVs that alter splicing or mRNA abundance. Moreover, many GVs with ASB patterns have known disease relevance. Overall, BEAPR is an effective method that helps to address the outstanding challenge of functional interpretation of GVs. Differential binding of RNA-binding proteins mediated by genetic variants (GVs) can influence posttranscriptional regulation. Here, the authors develop BEAPR, a computational approach to identify allele-specific binding events in eCLIP-Seq data.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-019-09292-w