Genomic Competition for Noise Reduction Shaped Evolutionary Landscape of Mir-4673

Abstract

AbstractThe genomic platform that informs evolution of microRNA cascades remains unknown. Here we capitalized on the recent evolutionary trajectory of hominin-specific miRNA-4673 (Dokumcu et al., 2018) encoded in intron 4 of notch-1 to uncover the identity of one such precursor genomic element and the selective forces acting upon it. The miRNA targets genes that regulate Wnt/β-catenin signalling cascade. Primary sequence of the microRNA and its target region in Wnt modulating genes evolved from homologous signatures mapped to homotypic cis-clusters recognised by TCF3/4 and TFAP2A/B/C families. Integration of homologous TFAP2A/B/C cis-clusters (short range inhibitor of β-catenin (Li and Dashwood, 2004)) into the transcriptional landscape of Wnt cascade genes can reduce noise in gene expression (Blake et al., 2003). Probabilistic adoption of miRNA secondary structure by one such cis-signature in notch-1 reflected selection for superhelical curvature symmetry of precursor DNA to localize a nucleosome that overlapped the latter cis-cluster. By replicating the cis-cluster signature, non-random interactions of the miRNA with key Wnt modulator genes expanded the transcriptional noise buffering capacity via a coherent feed-forward loop mechanism (Hornstein and Shomron, 2006). In consequence, an autonomous transcriptional noise dampener (the cis-cluster/nucleosome) evolved into a post-transcriptional one (the miRNA). The findings suggest a latent potential for remodelling of transcriptional landscape by miRNAs that capitalize on non-random distribution of genomic cis-signatures.