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Researchers at the University of Toronto have discovered a genetic network linked to autism. The results will facilitate the development of new treatments for this common neurological disorder.
As part of a collaborative autism research program led by Benjamin Blencowe, Professor at the Donnelly Center for Cellular and Biomolecular Research at the University of Toronto, Thomas Gonatopoulos-Pournatzis Postdoctoral Fellow, lead author of the study, has uncovered a network of more than 200 genes involved in the control of alternative splicing events often disrupted in autism spectrum disorders (ASD).
Alternative splicing is a process that functionally diversifies protein molecules – the building blocks of cells – into the brain and other parts of the body. Blencowe's laboratory had previously shown that the disruption of this process was closely related to changes in cerebral cabling and behavior in autism.
Microexons
Better known for its effects on social behavior, it is thought that autism is caused by cerebral cabling problems established during embryo development.
"Our study revealed a mechanism underlying splicing of very short coding segments found in genes with genetic links to autism. This new knowledge allows to better understand the possible ways to target this mechanism for therapeutic applications ",
says Blencowe, who is also a professor in the Department of Molecular Genetics and holds the Banbury Chair in Medical Research at the University of Toronto.
Hundreds of genes have been linked to autism, making its genetic bases difficult to unravel. The alternative splicing of small gene fragments, or microexons, became a rare unifying concept in the molecular basis of autism after Blencowe's team discovered that microexons were disrupted in a large proportion of autistic patients.
As tiny segments of genes encoding proteins, microexons have an impact on the ability of proteins to interact with one another when forming neural circuits. Microexons are particularly critical in the brain, where they are included in the RNA template for protein synthesis during the splicing process.
Splicing allows the use of different combinations of protein-encoding segments, or exons, as a means of enhancing the functional repertoires of protein variants in cells.
Screening with CRISPR
Although scientists are well aware of how exons, which contain about 150 letters of DNA, are spliced, it has not been determined how micro-exons, much smaller – from 3 to 27 letters of DNA – are used. in the nerve cells.
"The small size of microexons" presents a challenge for splicing machines and it is a puzzle that has long made these little exons are recognized and spliced, "
Blencowe said.
To answer this question, Gonatopoulos-Pournatzis has developed a method of identifying genes involved in the splicing of microexons.
Using the powerful CRISPR gene editing tool and collaborating with Mingkun Wu and Ulrich Braunschweig in the Blencowe lab as well as with Jason Moffat's lab at the Donnelly Center, Gonatopoulos-Pournatz took out brain cells grown each of the 20,000 genes of the gene to be found. which ones are needed for microexon splicing. He identified 233 genes whose various roles suggest that microexons are regulated by a vast network of cellular components.
"One of the really important benefits of this screen is that we have been able to capture the genes that affect the splicing of microexons both directly and indirectly and to learn how various molecular pathways influence this process,"
Blencowe said.
nSR100 / SRRM4
Gonatopoulos-Pournatzis has been able to find other factors that work closely with a major microexon splicing regulator already identified, a protein called nSR100 / SRRM4, previously discovered in Blencowe's lab. In collaboration with the team of Anne-Claude Gingras of the Lunenfeld-Tanenbaum Research Institute of the Sinai Health System, they identified proteins called Srsf11 and Rnps1 as forming a molecular complex with nSR100.
Knowing the precise molecular mechanisms of microexon splicing will help guide future efforts to develop a therapeutic potential for autism and other disorders. For example, since the splicing of microexons is disrupted in autism, researchers could look for drugs that can restore their levels to those seen in unaffected individuals.
"We now understand better the mechanism of recognition and splicing of microexons in the brain. When you know the mechanism, you can potentially target it by using rational approaches to develop therapies for neurodevelopmental disorders,
said Gonatopoulos-Pournatzis.
Thomas Gonatopoulos-Pournatzis, Wu Mingkun, Ulrich Braunschweig, Jonathan Roth, Han Hong, Andrew J. Best, Raj Bushra, Michael Aregger, Dave O. Hanlon, Jonathan D. Ellis, John A. Calarco, Jason Moffat and Anne- Claude Gingras Benjamin J. Blencowe
A CRISPR-Cas9 interrogation of the genome on splicing networks reveals a mechanism of recognition of neural microexons disordered by autism
Molecular Cell Volume 72, Number 3, p510-524.E12, 01 November 2018
Image: Thomas Gonatopoulos-Pournatzis
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