Discovery of Allele-Specific Protein-RNA Interactions in Human Transcriptomes

Am J Hum Genet. 2019 Mar 7;104(3):492-502. doi: 10.1016/j.ajhg.2019.01.018. Epub 2019 Feb 28.

Abstract

Gene expression is tightly regulated at the post-transcriptional level through splicing, transport, translation, and decay. RNA-binding proteins (RBPs) play key roles in post-transcriptional gene regulation, and genetic variants that alter RBP-RNA interactions can affect gene products and functions. We developed a computational method ASPRIN (Allele-Specific Protein-RNA Interaction) that uses a joint analysis of CLIP-seq (cross-linking and immunoprecipitation followed by high-throughput sequencing) and RNA-seq data to identify genetic variants that alter RBP-RNA interactions by directly observing the allelic preference of RBP from CLIP-seq experiments as compared to RNA-seq. We used ASPRIN to systematically analyze CLIP-seq and RNA-seq data for 166 RBPs in two ENCODE (Encyclopedia of DNA Elements) cell lines. ASPRIN identified genetic variants that alter RBP-RNA interactions by modifying RBP binding motifs within RNA. Moreover, through an integrative ASPRIN analysis with population-scale RNA-seq data, we showed that ASPRIN can help reveal potential causal variants that affect alternative splicing via allele-specific protein-RNA interactions.

Keywords: CLIP-seq; RNA-seq; alternative splicing; bioinformatics; genetic variation; post-transcriptional regulation; protein-RNA interactions; single-nucleotide polymorphism; transcriptomics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Alternative Splicing
  • Computational Biology / methods*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • RNA / genetics
  • RNA / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Sequence Analysis, RNA / methods*
  • Transcriptome*

Substances

  • RNA-Binding Proteins
  • RNA