Structure and Constraints Imposed on the Network of miRNA Mediated Regulation of RNA-Binding Proteins in the Human Genome

Abstract

MicroRNAs (miRs) and RNA-binding proteins (RBPs) mediate post transcriptional regulation with uncharacterized communication among themselves on a global scale, thus amplifying a new level of complexity of gene expression and regulation. In this study, we aimed to investigate the miR control over RBPs with respect to non-RBPs, at transcript level and its impact at protein level. We predicted miR targeted transcripts on a genome-wide scale using TargetScan and miRanda algorithms and calculated the proportion of target transcripts (separately for RBPs and non-RBPs) controlled by each miRs. Such genome wide miR-mRNA networks were analyzed for their impact on (a) targeted transcripts' expression [Human body map RNA sequence data, quantified by SAILFISH] pattern across 1.6 tissue type (b} RBPs' transcript half life [HEK293] and (c) targets' protein abundance (Human Protein Atlas) pattern across 9, tissue types, using eq1ual binning approach with respect to degree of miR reg1ulation. We observed that the proportion of RBP transcripts controlled by miRs was significantly different than that for Non-RBP' transcripts (p-value < 2.2e-16). The number of RBP transcripts controlled by miRs exhibit scaling distribution with more than 50% of uniquie RBP transcripts targeted by 0.3% of the miRNAs. miRs extensively regulating RBP transcripts included miR-4739, miR-4728-Sp, miR-608, miR-149-3p while 52% of RBP transcripts were targeted by 28% weakly regulating miRs. miRs exhibit a consistent controlling pattern over RBPs (further supported by half lives) and non-RBPs at transcript level in all tissue types, further justifying their involvement in degradation/destabilization. However miRs have no significant influence over RBPs' protein level when compared to Non-RBPs. miRs were found altering the RBPs' transcript level, while the protein levels remained unaltered across tissues possibly suggesting an uncharacterized buffering mechanism which maintains high protein levels for RBPs. Our study therefore puts forward a means by which high translation rate for RBP transcripts can ensure just-in-time protein production of RBPs across tissue types.