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Microexon Study Reveals Potential Misregulation in Autism Brain Tissue

NEW YORK (GenomeWeb) – A study appearing online today in Cell hints that individuals with autism spectrum disorder may be prone to misregulation of alternatively spliced gene snippets known as microexons — particularly those regulated in ways that influence brain development and function.

"Microexons are an underappreciated class of splicing event that is highly conserved," University of Toronto molecular genetics researcher Benjamin Blencowe said in a statement. "They change the way proteins interact and clearly play an important role in development, so understanding their role in human neurological disorders represents a major avenue of future research."

Blencowe and colleagues from Canada, the US, UK, and Spain used an RNA sequencing and analysis pipeline to identify some 2,500 alternative splicing events that appear to be subject to brain-specific regulation in mice or in humans, based on transcript patterns in more than 50 cell lines or tissue samples from the two mammalian species.

They found that more miniscule alternative splicing events — so-called microexons spanning a few to a few dozen nucleotides — typically exhibited high levels of conservation and regulation across the mammalian tissue types and developmental stages considered.

Those features appeared especially pronounced in the case of microexons exhibiting neural regulation, which also tended to be short even by microexon standards.

"These data reveal the largest program of neural-regulated [alternative splicing] events defined to date," Blencowe and co-authors wrote, and "this program is associated with a broader range of functional processes and pathways linked to nervous system biology than previously detected."

The team noted that almost half of the subtle changes in neural gene splicing seem to subtly alter the resulting protein isoforms, producing proteins with somewhat different interaction partners in the brain's highly interconnected protein networks.

The microexons "modify proteins — changing their surface structures — in ways that longer exons cannot," first author Manuel Irimia, a postdoctoral researcher affiliated with the University of Toronto and Spain's Centre for Genomic Regulation, said in a statement. "Microexons perform a type of microsurgery on proteins to alter their function."

When the team compared RNA profiles in post-mortem brain tissue samples from a dozen individuals with ASD and as many unaffected controls, it saw what seemed to be more frequent misregulation in the ASD brain samples.

For those experiments, the team initially sequenced RNA transcripts in superior temporal gyrus brain region samples from 24 deceased individuals with ASD and 24 unaffected controls.

From there, researchers focused in on the 12 individuals "with the strongest ASD-associated differential gene expression signature" and 12 controls with near median RNA transcript patterns.

In that subset of samples, the team saw ASD-related microexon differences involving nearly one-third of the microexons considered. And most of those distinctly regulated microexons belonged to the neural-associated microexon set.

On the other hand, just over 5 percent of the longer alternatively spliced exons exhibited apparent regulatory differences in the ASD and control brain tissue samples. Again, though, one-third of those belonged to the collection of exons with neural regulation.

In a series of follow-up experiments, the researchers used quantitative RT-PCR and other approaches to demonstrate that the ASD brain samples showed decreased expression of the neuronally active splicing factor nSR100, on average, consistent with the idea that the regulation of microexons may be unusual in brain tissue from at least some individuals with ASD. 

"While a lot more work has to be done to understand the functions of microexons in the nervous system, we were amazed by the extent to which microexons are misregulated in people with autism, which suggests they are an important component of this neurological disorder," Blencowe said in a statement.