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. 2020 Sep 8:11:515094.
doi: 10.3389/fgene.2020.515094. eCollection 2020.

A Survey of Regulatory Interactions Among RNA Binding Proteins and MicroRNAs in Cancer

Ying Liu  1   2 , Chu Pan  1   2 , Dehan Kong  3 , Jiawei Luo  1 , Zhaolei Zhang  2   4   5
Affiliations

A Survey of Regulatory Interactions Among RNA Binding Proteins and MicroRNAs in Cancer

Ying Liu et al. Front Genet. .

Abstract

Recent advances in genomics and proteomics generated a large amount of trans regulatory data such as those mediated by RNA binding proteins (RBPs) and microRNAs. Since many trans regulators target 3' UTR of mRNA transcripts, it is likely that there would be interactions, i.e., competitive or cooperative effect, among these trans factors. We compiled the available RBP and microRNA binding sites, mapped them to the mRNA transcripts, and correlated the binding data with mRNA expression data generated by The Cancer Genome Atlas (TCGA). We separated pairs of RBPs and microRNAs into three scenarios: those that have overlapping target sites on the same mRNA transcript (overlapping), those that have target sites on the same mRNA transcript but non-overlapping (neighboring), and those that do not target the same mRNA transcript (independent). Through a regression analysis on expression profiles, we indeed observed interaction effect between RBPs and microRNAs in the majority of the cancer expression data sets. We further discussed implication of such widespread interactions in the context of cancer and diseases.

Keywords: RNA binding proteins; cancer; gene expression; gene regulation; microRNAs; regression analysis.

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Figures

FIGURE 1
FIGURE 1
(A) Three different scenarios between two trans regulators. In scenario 1 (Overlapping), both trans regulators target the same mRNA transcript with overlapping binding sites. In scenario 2 (Neighboring), both trans regulators target the same mRNA transcripts but the binding sites do not overlap. In scenario 3 (Independent), the two trans regulators do not bind to the same transcript. (B) A flowchart on determining RBP binding sites.
FIGURE 2
FIGURE 2
Summary of RBP binding sites. (A) Number of RBP binding sites per gene, binding sites from different RBPs are pooled together. X-axis represents the number of RBP binding sites per gene and the last column represents the number of genes with total binding sites greater than 1000, Y-axis indicates the number of genes that have that number of RBP binding sites. (B) Number of unique RBPs that bind to a human gene. X-axis indicate the number of unique RBPs bound to one mRNA, Y-axis indicates the number of genes.
FIGURE 3
FIGURE 3
Overlap among RBP binding sites after sequentially removing RBPs with the highest number of binding sites. The red circles represent real observed data while the black circles represent averaged results over 10 rounds of random simulation.
FIGURE 4
FIGURE 4
RBPs that have overlapping or neighboring binding sites. Color in each cell indicates the number of mRNAs on which the two RBPs have overlapping or neighboring binding sites. RBPs are listed in the same order on both X- and Y-axis. The top overlapping pairs in the top left corer are magnified in the inset.
FIGURE 5
FIGURE 5
Summary of microRNA binding sites. (A) Total number of microRNA binding sites per gene, binding sites of different microRNAs are pooled together. X-axis represents the number of microRNA binding sites per gene and the last column represents the number of genes with binding sites greater than 100, Y-axis indicates the number of genes that have that number of microRNA binding sites. (B) Number of unique microRNAs that bind to a human gene. X-axis represents the number of microRNA binding sites per gene and the last column represents the number of genes with binding sites greater than 100, Y-axis indicates the number of genes.
FIGURE 6
FIGURE 6
RBPs and microRNAs that have overlapping or neighboring binding sites. RBPs are listed on the Y-axis and microRNAs are listed on the X-axis. Color in each cell represents the number of genes on which the RBP and the microRNA have overlapping (A) or neighboring (B) binding sites. As the result of clustering, the order of RBPs or microRNAs are different between left and right panels.
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