CircRNP complexes:from nature to design

Circular RNAs(circRNAs)have recently been established as a new and large class of noncoding RNAs,conserved in all eukaryotes investigated.However,functional and mechanistic investi-gations lag behind the rapid progress in circRNA expression studies,and no uniform function has emerged so far.Here,we focus on circRNA–protein(circRNP)complexes(circRNPs),since proteins associated with natural circRNAs likely guide us in the search for physiological functions of individual circRNAs.First,approaches for how to systematically search for circRNA-interacting proteins in natural circRNPs will be summarized,including some experimental considerations important for good scientific practice.Second,building on natural protein-sponging circRNAs,we introduce the concept of designer circRNAs functioning as specific protein sponges,using the heterogeneous nuclear ribonucleoprotein L(hnRNP L)and IMP3 proteins as two examples of classical RNA-binding proteins.Third,we discuss the general implications of this concept,in particular how it can be applied as a new way to intervene with RNA-based gene-regulatory networks.In sum,designer circRNAs sponging specific proteins open up exciting new perspectives in molecular medicine and on therapeutic options to treat human disease.