MicroRNAs with close or overlapping target sites are often highly conserved and can play a role in lupus and other diseases, according to a study in BMC Biology this week. MiRNAs are small, non-coding RNAs that bind to and repress specific mRNAs, and their dysfunction has been linked to a range of diseases. Multiple miRNAs can target closely spaced target sites to achieve stronger mRNA repression, but the pathological significance of such cotargeting is unknown. To investigate, a team led by Nagoya University researchers performed miRNA expression profiling in a mouse model of systemic lupus erythematosus and identified two miRNAs — miR-128 and miR-148a — that were downregulated in certain immune cells highly implicated in the disease. Further analysis revealed that the two miRNAs target a pro-inflammatory transcription factor via extensively overlapping target sites to suppress inflammatory responses. The study's authors also demonstrated that such overlap is prevalent among broadly conserved miRNAs and their target sites, and they uncovered two major conservation classes of target sites: those conserved among eutherian mammals and between humans and the bony fish Coelacanth. "These findings highlight the importance of perturbed miRNA cotargeting in human pathology and unique evolutionary aspects of miRNA cotargeting and miRNA target site conservation," they write.