Regulation of Cell-Type-Specific Transcriptomes by miRNA Networks During Human Brain Development

MicroRNAs (miRNAs) regulate many cellular events during brain development by interacting with hundreds of mRNA transcripts. However, miRNAs operate non-uniformly upon the transcriptional profile with an as yet unknown logic. Shortcomings in defining miRNA-mRNA networks are limited knowledge of in vivo miRNA targets, and their abundance in single cells. By combining multiple complementary approaches, AGO2-HITS-CLIP, single-cell profiling, and innovative computational analyses using bipartite and co-expression networks, we show that miRNA-mRNA interactions operate as functional modules that often correspond to cell-type identities and undergo dynamic transitions during brain development. These networks are highly dynamic during development and over the course of evolution. One such interaction is between radial glia-enriched ORC4 and miR-2115, a great ape specific miRNA, which appears to control radial glia proliferation rates during human brain development.