Concerted loss of microRNAs uncovers multi-level restructuring of gene regulation in rodents
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MicroRNAs (miRNAs) are post-transcriptional regulators involved in key biological processes. Lineage-specific losses of multiple miRNA families during evolution are rare. If they occur, they often coincide with significant changes in gene regulation with consequences extending to body plan modifications. Recently, 15 mammalian miRNA families were found missing in the Eumuroidea , including mouse and rat. It remains unknown to what extent this has affected the gene regulatory network in this lineage. Here, we shed light on the implications of these losses. We integrate in silico characterizations of these miRNAs with differential gene expression analyses in human and mouse inducible pluripotent stem cells (iPSCs) overexpressing two representatives, Mir-197 and Mir-769. This revealed that partly the same genes are downregulated in response to the miRNA overexpression in mouse and human. We dated the emergence of the miRNA target sites in the corresponding transcripts to before the mammalian divergence. Therefore, the response to miRNA overexpression in mouse iPSCs likely represents remnants of an ancient gene regulatory network that existed already in the last common ancestor of human and mouse. This provides strong evidence that the miRNA loss disrupted established regulatory connections in Eumuroidea . Notably, we detected an accompanying loss of at least 37 transcription factors in in this lineage. Thus, Eumuroidea have modified their gene regulatory networks on two levels, transcriptionally and post-transcriptionally. It will now be interesting to precisely chart the differences in gene regulation and how this affects the use of mouse and rat as model systems for human disease.
Author summary
The phenotypic specifics of a species are jointly determined by its sets of structural and regulatory genes, where the latter control gene expression in a spatial and temporal manner. Micro-RNAs (miRNAs) are short regulatory genes and alter gene expression post-transcriptionally. Over evolutionary timescales, they are rarely lost in larger numbers on individual lineages, highlighting their functional relevance. The model species mouse and rat, together with their relatives in the Eumuroidea lack 15 miRNA families that are otherwise largely conserved throughout the mammals. If, and to what extent, the corresponding gene loss has affected gene regulation in the last common ancestor of Eumuroidea is unknown. Here, we provide evidence that the corresponding loss of miRNA genes is not compensated by other genes. We trace remnants of the ancestral regulatory network under control of two miRNAs in mouse, providing first time evidence that the miRNA loss in the Eumuroidea must have had consequences for gene expression regulation. We further show that protein-coding genes that have been co-lost with the 15 miRNAs are enriched for transcription factors. Jointly, this reveals that the diversification of Eumuroidea during mammalian evolution was accompanied by a change in gene expression regulation on the transcriptional and post-transcriptional level.
