Generally, pre-mRNA transcribed by RNA polymerase II (Pol II) contains introns and exons, followed by a 7- methylguanosine cap and poly-adenosine tail adding to its 5′- and 3′-ends, respectively. Then with the assist- ance of spliceosomes, pre-mRNA undergoes splicing at canonical splice sites (5′-GU and 3′-AG at introns) to become mature and translatable. CircRNA is generated by a special alternative splicing manner termed back- splicing, in which the 3′-end of an exon ligates to the 5′-end of its own or an upstream exon through a 3′,5′- phosphodiester bond, forming a closed structure with a back-splicing junction site [7, 8, 26]. Initially, circRNAs were regarded as splicing errors containing so-called “scrambled exons” [27].According to the order of splicing events and different intermediates, two models of biogenesis were proposed [28] and validated [29]: the lariat model and the direct back-splicing model [26]. Recently, an excellent study as- sembled the spliceosome E complex on pre-mRNA and carried out structural and biochemical analyses, propos- ing an integral model for intron definition, exon defin- ition, remodeling and the back-splicing-mediated circRNA biogenesis [30].