Tuesday, September 23, 2014

The Production of Circular RNA Competes with Normal RNA Processing in Cells

All of our genetic information is encoded in DNA.  In order for genes to be expressed as functional proteins in our cells, they must first be copied (or transcribed) into single-stranded RNA molecules, known as messenger RNA (mRNA).  These genetic instructions are then translated into amino acid sequences that make up proteins.  Recently, a new type of RNA was discovered that forms in a closed, continuous loop, rather than in a linear molecule - known as circular RNA (circRNA).  It turns out that circRNA are abundant in cells, but they are very poorly understood.  Despite this, these RNA molecules seem to play a role in the development and progression of degenerative diseases.  A recently published study from the Hebrew University of Jerusalem has given us a better idea of how circRNA are produced in the cell.
When mRNA is produced, it copies the whole gene that is being expressed.  But many genes contain non-coding sequences, called introns.  Post-transcriptional modifications of mRNA remove these introns - in a process called splicing - fusing the remaining exons together.  These modifications also add a poly-adenine tail and a 5' cap, both of which protect the mRNA molecule from degradation.

Only two circRNA, out of the thousands found across the animal kingdom, have had their functions elucidated.  These two (CDR1as/ciRS-7 and Sry) act as competitive inhibitors to microRNA (miRNA).  Since miRNA are non-coding, but influence gene expression and silencing, it is predicted that circRNA may play similar roles as antagonists to miRNA.  However, since CDRIas/ciRS-7 is really good at taking miRNA out of commission, with 70 binding sites, there are some scientists who predict that circRNA may have other functions as well, including RNA and protein transport.

The authors of this study, led by Dr. Sebastian Kadner, demonstrated that circRNA are generated cotranscriptionally - that is, they are a form of mRNA, where the 5' end of the molecule attacks and covalently binds with the 3' end, forming a circle.  The formation of circRNA is dependent on the introns flanking the splice site, and this competes with the production of normal mRNA.  The production of circRNA has a negative effect on gene expression.  That means that circRNA add yet another layer of complexity in gene expression, because by competing with the normal mRNA processing, the balance between normal mRNA and circRNA influences which genes are expressed and which are not, and the level of expression.

They also found that circRNA are highly produced in brain cells.  In many cases, they also stem from genes that have very important functions.  The authors suggest that circRNA may be crucial to brain function, and play a key role in brain disease.  The gene that had the most circRNA associated with it is called muscleblind, expressed in the brain of fruit flies.  In the heads of fruit flies, muscleblind circRNA are more abundant than normal mRNA, and the authors showed that this gene can enhance and regulate the formation of its subset of circRNA molecules.

Interestingly, muscleblind is also involved in normal brain function, since defects in the sequence have been shown to cause a severe degenerative disease known as myotonic dystrophy.  This disease is characterized by progressive muscle wasting and weakness, and is the most common form of adult-onset muscular dystrophy.  The connection between muscleblind and circRNA suggests that these small RNA molecules may be involved in the development of myotonic dystrophy.

This study is really interesting because it not only deepens our understanding of molecular biology and the complexity of gene expression, but it also provides new avenues for studying and treating degenerative diseases of the brain and muscles.  Additionally, another study reported altered levels of CDR1as/ciRS-7 in patients with Alzheimer's disease, further supporting the idea that circRNA play a role in degenerative disease.  I'm looking forward to seeing more exciting results linking the two in the future!

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