In their newly published research, Zhang and Krainer used a comprehensive set of computational methods to predict how and where the splicing factors Fox-1 and Fox-2 attach, or bind, to unedited target RNA transcripts. "The effect of splicing factors on the activation or repression of splicing often depends on the location and context of the RNA sequences they bind," Dr. Krainer explained.
It was known that the two proteins have the ability to home in on a stretch of RNA that bears a specific code ("UGCAUG"), although the presence of this sequence on an RNA is not sufficient to guarantee binding by Fox-1/2 proteins. "Prior to our experiments, only a handful of targets of this kind had been determined experimentally," Dr. Zhang observed. An authority on the application of computational methods to biological questions, Zhang and members of his lab generated predictions about Fox-1 and Fox-2 after closely examining the genomes of 28 different vertebrate species.
From conserved networks to disease targets
Experimental follow-up in the Krainer lab of the predicted binding sites indicated that between one-half and three-fourths of the thousands of computational binding-site predictionsand the corresponding alternative splicing patternswere correct. The fact that the predicted targets were conserved during evolution across distantly related species suggests the relative importance of Fox-1 and Fox-2 function in many living systems. Indeed, the experiments confirmed that the regulatory networks that govern the actions of the splicing factors are also conserved across species.
Perhaps most important, the team found, in Zhang's words, that "many of the predicte
|Contact: Peter Tarr|
Cold Spring Harbor Laboratory