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RNA-binding proteins (RBPs) participate in all stages of RNA life cycle from transcription, splicing, to translation. Under the ENCODE project, a large number of RBPs were knocked down in human cancer cell lines, offering an excellent opportunity to infer targets of RBPs. Taking both RBP binding sites and RNA-seq profiles of RBP knockdown samples as input, we present a pipeline to identify causal RBP RNA interactions. The pipeline employs a recent functional chi-square test (FunChisq) that deciphers directional association, and utilizes a novel functional index that measures the effect size of functional dependency. We examined ∼45 million RBP RNA pairs in leukemia (K562) and liver cancer (HepG2) cell lines for functional patterns as causal interaction candidates. Here, we report a total of 936,707 RBP RNA pairs in the two cell lines that show statistically significant linear or nonlinear functional patterns. About 31% of these pairs have supportive biological evidence from other sources, suggesting the effectiveness of the pipeline. The interactions constitute RBP specific regulatory networks that may potentially represent core mechanisms in the two cancers. The pipeline is implemented through an R interface with pre-computed results and data libraries for users to query specific networks and visualize RBP RNA interactions. Such networks serve as a useful resource for studying RNA dysregulation in cancer.
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Improved modeling of RNA-binding protein motifs in an interpretable neural model of RNA splicing
Abstract Sequence-specific RNA-binding proteins (RBPs) play central roles in splicing decisions. Here, we describe a modular splicing architecture that leverages in vitro-derived RNA affinity models for 79 human RBPs and the annotated human genome to produce improved models of RBP binding and activity. Binding and activity are modeled by separate Motif and Aggregator components that can be mixed and matched, enforcing sparsity to improve interpretability. Training a new Adjusted Motif (AM) architecture on the splicing task not only yields better splicing predictions but also improves prediction of RBP-binding sites in vivo and of splicing activity, assessed using independent data.
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- Award ID(s):
- 1918839
- PAR ID:
- 10486175
- Publisher / Repository:
- Springer Science + Business Media
- Date Published:
- Journal Name:
- Genome Biology
- Volume:
- 25
- Issue:
- 1
- ISSN:
- 1474-760X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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