CircRNAs

Circular RNAs are a class of stable RNA molecules formed when the spliceosome joins a downstream 5′
splice site to an upstream 3′ splice site (“backsplicing”), yielding a covalently closed RNA circle . They
were once thought rare, but circRNAs are now known to be widespread and abundant in the brain .
The Kadener Lab has made pioneering contributions to circRNA biology. Notably, circRNAs are produced
co-transcriptionally in competition with normal (linear) splicing, so their biogenesis can regulate
gene expression of the host gene . For example, the lab showed that the splicing factor MBL
(Muscleblind) binds its own pre-mRNA to promote circularization of one exon, thereby reducing linear
mRNA – a feedback mechanism that tunes Mbl gene expression . This discovery, first demonstrated with
a circRNA generated from the muscleblind gene, revealed that circRNA formation can modulate protein
output from important regulators (a form of cis-regulation) . The lab’s 2014 study “circRNA biogenesis
competes with pre-mRNA splicing” provided a foundation for this concept .
In addition to affecting their host genes, circRNAs can also act in trans to influence other molecular
pathways. Some circRNAs function as molecular sponges for microRNAs or RNA-binding proteins,
sequestering these regulators away from their targets . A famous example is CDR1as (ciRS-7), a circRNA
that contains dozens of binding sites for miR-7, thereby modulating neuronal activity . Kadener Lab’s
work in flies demonstrated that knockdown of a brain-expressed circRNA (circMbl) leads to locomotor
activity defects in Drosophila , indicating circRNAs can influence neural circuit function and behavior.
Moreover, the team has shown that some circRNAs are translated into proteins, expanding their functional
potential beyond noncoding roles . In a 2017 study, they provided evidence that certain Drosophila
circRNAs are associated with ribosomes and can produce detectable peptides . This finding was
groundbreaking, revealing that circRNAs can encode proteins – an entirely new layer of gene expression
regulation.