Single nucleotide polymorphisms affect RNA-protein interactions at a distance through modulation of RNA secondary structures

Elan Shatoff; Ralf Bundschuh

doi:10.1371/journal.pcbi.1007852

Single nucleotide polymorphisms affect RNA-protein interactions at a distance through modulation of RNA secondary structures

PLoS Comput Biol. 2020 May 7;16(5):e1007852. doi: 10.1371/journal.pcbi.1007852. eCollection 2020 May.

Authors

Elan Shatoff^{1

2}, Ralf Bundschuh^{1

2

3

4}

Affiliations

¹ Department of Physics, The Ohio State University, Columbus, Ohio, United States of America.
² Center for RNA Biology, The Ohio State University, Columbus, Ohio, United States of America.
³ Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio, United States of America.
⁴ Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America.

Abstract

Single nucleotide polymorphisms are widely associated with disease, but the ways in which they cause altered phenotypes are often unclear, especially when they appear in non-coding regions. One way in which non-coding polymorphisms could cause disease is by affecting crucial RNA-protein interactions. While it is clear that changing a protein binding motif will alter protein binding, it has been shown that single nucleotide polymorphisms can affect RNA secondary structure, and here we show that single nucleotide polymorphisms can affect RNA-protein interactions from outside binding motifs through altered RNA secondary structure. By using a modified version of the Vienna Package and PAR-CLIP data for HuR (ELAVL1) in humans we characterize the genome-wide effect of single nucleotide polymorphisms on HuR binding and show that they can have a many-fold effect on the affinity of HuR binding to RNA transcripts from tens of bases away. We also find some evidence that the effect of single nucleotide polymorphisms on protein binding might be under selection, with the non-reference alleles tending to make it harder for a protein to bind.

Publication types

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

MeSH terms

Genome, Human
Humans
Nucleic Acid Conformation*
Polymorphism, Single Nucleotide*
Protein Binding
RNA, Messenger / chemistry
RNA, Messenger / metabolism*
RNA-Binding Proteins / metabolism*

Substances

RNA, Messenger
RNA-Binding Proteins

Grants and funding

ES and RB were supported by the National Science Foundation (https://www.nsf.gov) under grant no. DMR-1719316 to RB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.