Critical analysis of the hypothesized SNHG1/miR-195-5p/YAP1 axis

Abstract

How lncRNAs such as SNHG1 are integrated into cellular pathways to regulate, or be a regulatory component of, cellular processes is a question yet to be completely answered.A potential mechanism by which SNHG1 may exert its effect is through the so-called sponge effect.In this mechanism, SNHG1 (or other lncRNAs) is thought to bind miRNAs as a molecular sponge in a sequence-specific manner and inhibit their ability to bind and inhibit translation of a specific mRNA.The recent paper by Cheng et al. (Cheng et al. 2022) makes just these connections, in this case, between SNHG1, miRNA-195-5p, and the Hippo pathway gene, YAP1.In their proposed model, miRNA-195-5p binds to, and causes degradation of, YAP1 mRNA.MiRNA-195-5p is in turn modulated through the sponging activity of SNHG1.These interactions theoretically occur through a region of 7 nucleotide complementarity.Thus, YAP1 target protein expression can be modulated through a complex interplay involving the degree of SNHG1 and miR-195-5p expression.High SNHG1 should lead to greater sponging of miR-195-5p, and result in high YAP1 mRNA and protein levels, and conversely, low SNHG1 should lead to less sponging of miR-195-5p, and therefore low YAP1 mRNA and protein levels.However, we would like to call attention to some aspects of the published study which are common in the field overall and to offer a counterpoint to the conclusions drawn.In the human genome, there are possibly 183,000 occurrences of the 7 nucleotide sequence being suggested to confer specificity in the binding of SNHG1 to miR-195-5p and, subsequently, YAP1 (calculated as the 3 billion bp human genome divided by the frequency of random appearance of the given 7 nt sequence -4 7 ).Within protein-coding regions, which are estimated to be 1.5% of the genome, there may be 2746 (4.5 × 10 7 /4 7 ) occurrences of this sequence.Indeed, miRNA target prediction websites (miRDB, miRDB.organd