skip to main content

Title: Scrutinizing functional interaction networks from RNA-binding proteins to their targets in cancer
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.  more » « less
Award ID(s):
Author(s) / Creator(s):
; ; ; ;
Date Published:
Journal Name:
2018 IEEE International Conference on Bioinformatics and Biomedicine (BIBM)
Page Range / eLocation ID:
185 - 190
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. RNA binding proteins (RBPs) regulate all aspects of RNA biogenesis from transcription, splicing, and translation to degradation, and they have a critical role in cellular homeostasis and functional diversity. Recent studies have indicated that altered expressions of RBPs are associated with many human diseases ranging from neurologic disorders to cancer. The transcriptional coregulator yes-associated protein 1 (YAP1), a critical nuclear effector of the mammalian Hippo pathway, regulates cell fate, cell contact, metabolism, and developmental processes. This study demonstrates a link between YAP1 and nucleophosmin1 (NPM1) protein. NPM1 is an RNA-binding protein that regulates many cellular activities, including ribosome biogenesis, RNA processing, chromatin remodeling, DNA repair, and genomic stability. We identified NPM1 from YAP1 protein complexes of androgen-responsive human cancer cells using proteomics approaches. Our proximity ligation assay demonstrated that YAP1 and NPM1 physically interacted with each other. The interaction between YAP1 and NPM1 occurred in cell nuclei and was regulated by androgen hormone signaling. In addition, our GST-pulldown assay demonstrated that NPM1 formed a protein complex with the proline-rich domain of YAP1. Furthermore, our enhanced RNA interactome capture (eRIC) assay showed that androgen also regulated the interaction of RBPs to polyA+ mRNA within the cell. Consistent with this observation, our eRIC assay combined with the mass spectrometry method enabled us to identify distinct RBP patterns in human cancer cells that are genetically related but phenotypically different. These observations indicate that global alterations of RBPs under changing environmental conditions may have essential roles in cellular physiology and disease biology. 
    more » « less
  2. 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.

    more » « less
  3. Abstract

    Nucleic acid-binding proteins (NABPs), including DNA-binding proteins (DBPs) and RNA-binding proteins (RBPs), play important roles in essential biological processes. To facilitate functional annotation and accurate prediction of different types of NABPs, many machine learning-based computational approaches have been developed. However, the datasets used for training and testing as well as the prediction scopes in these studies have limited their applications. In this paper, we developed new strategies to overcome these limitations by generating more accurate and robust datasets and developing deep learning-based methods including both hierarchical and multi-class approaches to predict the types of NABPs for any given protein. The deep learning models employ two layers of convolutional neural network and one layer of long short-term memory. Our approaches outperform existing DBP and RBP predictors with a balanced prediction between DBPs and RBPs, and are more practically useful in identifying novel NABPs. The multi-class approach greatly improves the prediction accuracy of DBPs and RBPs, especially for the DBPs with ~12% improvement. Moreover, we explored the prediction accuracy of single-stranded DNA binding proteins and their effect on the overall prediction accuracy of NABP predictions.

    more » « less
  4. Abstract

    The complexity of eukaryotic organisms is intricately tied to transcriptome‐level processes, notably alternative splicing and the precise modulation of gene expression through a sophisticated interplay involving RNA‐binding protein (RBP) networks and their RNA targets. Recent advances in our understanding of the molecular pathways responsible for this control have paved the way for the development of tools capable of steering and managing RNA regulation and gene expression. The fusion between a rapidly developing understanding of endogenous RNA regulation and the burgeoning capabilities of CRISPR‐Cas and other programmable RBP platforms has given rise to an exciting frontier in engineered RNA regulators. This review offers an overview of the existing toolkit for constructing synthetic RNA regulators using programmable RBPs and effector domains, capable of altering RNA sequence composition or fate, and explores their diverse applications in both basic research and therapeutic contexts.

    more » « less
  5. To cope with abiotic environmental stress, plants rapidly change their gene expression transcriptionally and post-transcriptionally, the latter by translational suppression of selected proteins and the assembly of cytoplasmic stress granules (SGs) that sequester mRNA transcripts. RNA-binding proteins (RBPs) are the major players in these post-transcriptional processes, which control RNA processing in the nucleus, their export from the nucleus, and overall RNA metabolism in the cytoplasm. Because of their diverse modular domain structures, various RBP types dynamically co-assemble with their targeted RNAs and interacting proteins to form SGs, a process that finely regulates stress-responsive gene expression. This review summarizes recent findings on the involvement of RBPs in adapting plants to various abiotic stresses via modulation of specific gene expression events and SG formation. The relationship of these processes with the stress hormone abscisic acid (ABA) is discussed. 
    more » « less