Neurogenetics study detects and identifies the function of microexons for the first time.


A study led by researchers from the University of Toronto and the Centre for Genomic Regulation has described a group of small DNA fragments that are key in neuron regulation and maturity.  The genome is the cell’s book of instructions. All the cells in the human body contain the same genomic information but each of them ‘reads’ the gene fragments that interest them in order to carry out their function.  The opensource study is published in the journal Cell.

Although neurons, hepatocytes and cardiac cells are different their genome is the same. In order to achieve this huge variety of functions from the same genome, the cells employ a mechanism known as alternative splicing. This enables them to combine several fragments,  known as exons, from the same genes in order to give rise to different proteins, in the same way that combinations of key words can create different phrases.

For years, the scientific community has been studying these ‘alternative’ exons that, when combined, give rise to different proteins. Until now, only alternative exons that are large enough to be detected by the available computational techniques were known.

The current study has not only been able to detect really small exons, known as ‘microexons’, but have also been able to determine their functions.   Microexons are very short fragments, some even code for only one or two amino acids, the basic components, or letters, of proteins, and the team have observed that these are essential for neuron maturation. In the same way that a word, even though very short, can change the meaning of a phrase, microexons acheive the same effect and contribute to the creation of proteins with different functions.

The team state that the nervous system is the only place where they found that the majority of microexons are activated, and discovered that they provide important functions in developing neurons. The team have also observed a relationship between these microexons and autism, a great number of the microexons studied are not expressed correctly in individuals with autism, including several microexons in genes that had previously been associated with this disorder.

On the other hand, identifying these microexons and demonstrating their functions provides new information for genome regulation and shakes the foundations of what, up to now, has been known about alternative splicing.  The medical community now knows that microexons change the way in which 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.

The group also observed that microexons have been highly conserved throughout vertebrate evolution. This surprised the researchers because it had always been shown that alternative exons were very plastic and, generally, not conserved in evolution. The fact that these microexons are so deeply conserved across vertebrates and that they play an important role in neuron maturation, could explain some of the large differences between vertebrates and invertebrates when it comes to the nervous system.

The team now plan to research the transcriptomics of vertebrate development and evolution, with view to understand the functions and evolutionary impact of alternative splicing on the nervous system of vertebrates.

Source:  The Centre for Genomic Regulation

Switch-like Regulation of Microexons during Neuronal Differentiation.  (A) Heatmap showing relative gene expression levels for key ESC and neural markers, including proneural genes (Neurog2 to Pax6) and postmitotic neuronal markers (Elavl3/HuC and Rbfox3/NeuN).  (B) Distribution of relative DPSI (DPSI divided by the PSI range across the six time points) for neural microexons and longer exons at each transition.  A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains.  Blencowe et al 2014.

Switch-like Regulation of Microexons during Neuronal Differentiation. (A) Heatmap showing relative gene expression levels for key ESC and neural markers, including proneural genes (Neurog2 to Pax6) and postmitotic neuronal markers (Elavl3/HuC and Rbfox3/NeuN). (B) Distribution of relative DPSI (DPSI divided by the PSI range across the six time points) for neural microexons and longer exons at each transition. A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains. Blencowe et al 2014.

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