MBG Focus Talk: Alexandra Bergfort

Many exons, one decision: the exon junction complex coordinates splicing — and hands us a puzzle

Splice-modifying drugs are entering the clinic, yet the underlying mechanism remains incompletely understood. Splicing is traditionally studied one exon at a time; cells do not always work that way. The exon junction complex (EJC) is deposited on mRNA as each intron is removed, leaving a protein mark at every exon–exon junction. Although best known for its later roles in mRNA export and nonsense-mediated decay, the EJC is loaded in the nucleus on nascent RNA, while neighboring introns are still being excised. We therefore asked whether it feeds back on splicing itself. Using long-read sequencing after rapid depletion of the EJC core protein EIF4A3, we find that neighboring exons are lost together: entire "exon blocks" disappear from the same mRNA molecule, in more than a thousand genes. Dissecting how the block is defined, however, hands us a puzzle — and an unexpected answer.