Integrating thermodynamic and sequence contexts improves protein-RNA binding prediction

PLoS Comput Biol. 2019 Sep 4;15(9):e1007283. doi: 10.1371/journal.pcbi.1007283. eCollection 2019 Sep.

Abstract

Predicting RNA-binding protein (RBP) specificity is important for understanding gene expression regulation and RNA-mediated enzymatic processes. It is widely believed that RBP binding specificity is determined by both the sequence and structural contexts of RNAs. Existing approaches, including traditional machine learning algorithms and more recently, deep learning models, have been extensively applied to integrate RNA sequence and its predicted or experimental RNA structural probabilities for improving the accuracy of RBP binding prediction. Such models were trained mostly on the large-scale in vitro datasets, such as the RNAcompete dataset. However, in RNAcompete, most synthetic RNAs are unstructured, which makes machine learning methods not effectively extract RBP-binding structural preferences. Furthermore, RNA structure may be variable or multi-modal according to both theoretical and experimental evidence. In this work, we propose ThermoNet, a thermodynamic prediction model by integrating a new sequence-embedding convolutional neural network model over a thermodynamic ensemble of RNA secondary structures. First, the sequence-embedding convolutional neural network generalizes the existing k-mer based methods by jointly learning convolutional filters and k-mer embeddings to represent RNA sequence contexts. Second, the thermodynamic average of deep-learning predictions is able to explore structural variability and improves the prediction, especially for the structured RNAs. Extensive experiments demonstrate that our method significantly outperforms existing approaches, including RCK, DeepBind and several other recent state-of-the-art methods for predictions on both in vitro and in vivo data. The implementation of ThermoNet is available at https://github.com/suyufeng/ThermoNet.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms
  • Computational Biology / methods*
  • Deep Learning
  • Gene Expression Regulation / genetics*
  • Humans
  • Protein Binding / genetics
  • RNA* / chemistry
  • RNA* / genetics
  • RNA* / metabolism
  • RNA-Binding Proteins* / chemistry
  • RNA-Binding Proteins* / genetics
  • RNA-Binding Proteins* / metabolism
  • Sequence Analysis, RNA / methods*
  • Thermodynamics

Substances

  • RNA-Binding Proteins
  • RNA

Grants and funding

This work was supported in part by the NSF CAREER Award (to J.P.) and the CompGen Fellowship (to Y. Luo). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.