The TRIM71 protein regulates the fates of mammalian stem cells. Although the protein has both RNA-binding and protein ubiquitylation activities, the molecular basis of its developmental function has been unclear. However, a well studied orthologue, LIN-41, in the model organism C. elegans provided potential hints as the Grosshans group (from the FMI in Basel) had previously shown that its known developmental functions were fully explained through binding and silencing of a small set of mRNA targets. Exemplifying the mission of the NCCR RNA & Disease to promote novel research avenues through collaboration among its members, the group now united its efforts with those of the Bühler group (also at the FMI) to understand whether this function was conserved for TRIM71 and to identify relvant targets. As reported in Genes & Development, the researchers used mouse embryonic stem cells to demonstrate that TRIM71, as in C. elegans, binds specific structures on target RNAs to silence them. “It was amazing to see that the way TRIM71/ LIN41 recognizes its targets in mammals is exactly the same as in worms,” says Alex Tuck, a postdoc in the Bühler group and one of the first authors of the study. “This nicely demonstrates the power of C. elegans as a model organism for studying core questions in biology.”
The obvious next step in the analysis was trying to get hold of relevant targets. Using various human and mouse cell lines, the researchers managed to identify several shared targets of TRIM71, including proteins involved in genetic disorders. Taking a closer look at one of them, MBNL1, they were able to show that the regulation of MBNL1 enables TRIM71 to take control of alternative splicing in stem cells, one possible mechanism to promote stem cell fates. Specific point mutations in TRIM71 were recently shown to cause a congenital brain disease, hydrocephalus, in humans. The FMI researchers discovered that these mutations impaired RNA target binding and silencing. While it remains unknown which specific TRIM71 target(s) mediate this disease phenotype, the team’s success in identifying targets shared across several mouse and human cell lines provides a springboard for further analysis, and “an important step towards understanding how mutations in TRIM71 can cause disease,” says Thomas Welte, a postdoc in the Großhans group and the other first author of the study.
Text: Roland Fischer