• CircRNA Biogenesis and Competition with Splicing: Our lab was among the pioneers in uncovering how circRNAs form. In a landmark study (Ashwal-Fluss et al., Molecular Cell 2014), they showed that circRNA production occurs co-transcriptionally and can compete with normal pre-mRNA splicing, meaning that generating a circRNA can occur at the expense of linear mRNA. They even identified a specific RNA-binding protein, Muscleblind (MBL), that promotes circRNA biogenesis from its own transcript – linking circRNA formation to a factor implicated in myotonic dystrophy. This finding was significant because it suggested circRNAs have a direct impact on gene expression and could be involved in disease when their biogenesis is misregulated.

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• CircRNAs in the Brain & Potential Roles: Kadener Lab and collaborators discovered that circRNAs are highly abundant in the nervous system. Many circRNAs are enriched in the brain and even specifically in synapses, hinting at roles in neuronal function. This was highlighted in our 2014 and 2015 study (Molecular Cell 2014, 2015) and others, where hundreds of brain-expressed circRNAs were catalogued. The abundance and conservation of circRNAs in brain tissue suggests they play important roles in brain function and possibly in neurological diseases. The lab often emphasizes that circRNA production is not just a byproduct, but a regulated process with likely regulatory roles itself.

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• CircRNA Translation into Proteins: Another breakthrough from the lab was the demonstration that circRNAs can encode proteins. In Molecular Cell 2017 (Pamudurti et al.), they provided the first evidence that a subset of circRNAs are loaded onto ribosomes and can be translated into peptides. This overturns the old assumption that circRNAs are noncoding – instead, some circRNAs have internal start codons or IRES elements that allow production of novel proteins. This expanded the horizon of the circRNA field, suggesting circRNAs might have dual lives as regulatory RNAs and templates for translation. The Kadener Lab’s work in this area was widely noted, underscoring the innovation of this research.​​

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• CircRNA Functions in Cells and Organisms: More recent research from the lab has started to elucidate what circRNAs do. For instance, circMbl, a circRNA from the Muscleblind gene, was shown to have regulatory functions both in cis (by competing with the linear mbl mRNA) and in trans (affecting other genes or phenotypes) depending on tissue. In a 2022 Cell Reports article, the team showed that circMbl interacts with its host gene in a feedback loop and also influences locomotor activity in flies, linking circRNA function to behavior. This indicates circRNAs can play active roles in physiological processes. Other circRNAs studied by the lab have been found to bind microRNAs (acting as “miRNA sponges”) or to interact with RNA-binding proteins, thereby influencing gene expression networks. The take-home message for this section: circRNAs are a major research focus of the lab, and the lab’s contributions – from discovering how they form, to showing they encode proteins, to uncovering their roles in neural function – have positioned them as leaders in circRNA biology.