Author and Curator: Ritu Saxena, Ph.D.
A recent post by Dr. Margaret Baker entitled “Junk DNA codes for valuable miRNAs: non-coding DNA controls Diabetes” talks about how the ENCODE project is revealing new insights into the functions of non-coding region of the human genome previously labeled as “junk DNA”. MicroRNA or miRNA, which as stated by Dr. Baker, “are among the non-gene encoding sequences in the genome and have been shown to play a major post-transcriptional role in expression of multiple genes.”
The post has touched upon several aspects of miRNA including origin, function, and mechanism of action. This commentary is an extension of Dr. Baker’s post, expanding upon the mechanism of action of miRNAs along with their role in potential disease therapy.
microRNA: Revisiting the past
MicroRNA were not discovered long back, infact, it was in 1998 when the presence of the non-coding RNAs that could be involved in switching ‘on’ and ‘off’ of certain genes. In the last decade, 2006 Nobel Prize for medicine or physiology was awarded to scientists Andrew Fire and Craig Mello for their discovery of this new role of RNA molecules.
A breakthrough research was published in the September 2010 issue of Nature journal, stating that mammalian microRNAs predominantly act by decreasing the levels of target mRNA. Mammalian microRNAs predominantly act to decrease target mRNA levels. miRNAs were initially thought to repress protein output without changes in the corresponding mRNA levels. Guo et al challenged the previous notion of ‘translational repression’ and concluded on the basis of their experimental results that ‘mRNA-destabilization’ scenario for the major part is responsible for the repression in protein expression via miRNAs. Authors utilized the method of ‘ribosome profiling’ to measure the overall effects of miRNA on protein production and then compared these to simultaneously measured effects on mRNA levels. Ribosome profiling prepares maps that exact positions of ribosomes on transcripts after nucleases chew upon the exposed part of transcripts that are not covered by ribosomes. MiR-1 and miR-155 were introduced into the HeLa-cell line. Both of these miRNAs are not normally expressed in HeLa cells. Another miRNA used was mir-223 which is expressed in significant amounts in neutrophils. The reason for choosing the set of these miRNAs was that they had already been shown to repress protein levels via proteomics research. It was deciphered that miRNA-mediated repression was similar regardless of target expression level and further stated that “for both ectopic and endogenous miRNA regulatory interactions, lowered mRNA levels account for lowered mRNA levels accounted for most for most (>/=84%) of the decreased protein production.” These results show that changes in mRNA levels closely reflect the impact of miRNAs on gene expression and indicate that destabilization of target mRNAs is the predominant reason for reduced protein output.
Authors concluded that the discovery “will apply broadly to the vast majority of miRNA targeting interactions. If indeed general, this conclusion will be welcome news to biologists wanting to measure the ultimate impact of miRNAs on their direct regulatory targets.”
Since then and even before the paper was published, several other miRNAs and their roles have been discovered. Information on miRNAs has been consolidated in a database that can be accessed online at http://www.mirbase.org/
microRNA: From bench to bedside
Scientific community had speculated the role of non-coding RNAs in disease treatment right after their discovery. One such study demonstrating the utilization of microRNA for Cancer treatment was published in the September 2010 issue of the journal Nature Medicine. miR-380-5p represses p53 to control cellular survival and is associated with poor outcome inMYCN-amplified neuroblastoma
The p53 gene is known as a tumor suppressor gene and its inactivation has been associated in some cancers such as neuroblastoma. The study reported that microRNA-380 (miR-380) was able to repress the expression of p53 gene in cancer patients causing uninhibited cell survival and proliferation. The research group was able to decrease the tumor size in vivo in a mouse model of the neuroblastoma by delivering miR-380 antagonist. The researchers also observed that the inhibition of endogenous miR-380 in embryonic stem or neuroblastoma cells resulted in induction of p53, and extensive apoptotic cell death.
Thus, the success of miR antagonist for decreasing tumor size speaks of the effectiveness of miR as a potential therapeutic target for cancer treatment.
In conclusion, as stated by Dr. Baker in her post, “the miRNA data for tissues and specific cell types involved in disease pathology form a new approach to either detecting or possibly correcting gene (coding or non-coding) dysregulation. miRNA mimics and anti-miRNA agents are being developed as new therapeutic modalities.”
Reference:
Pharmaceutical Intelligence post, Author, Dr. Margaret Baker: Junk DNA codes for valuable miRNAs: non-coding DNA controls Diabetes
http://pharmaceuticalintelligence.com/2012/09/24/junk-dna-codes-for-valuable-mirnas/
Research articles: Mammalian microRNAs predominantly act to decrease target mRNA levels
Expert reviews- miRNA and Cancer treatment
News briefs: http://ygoy.com/2010/10/02/new-treatment-for-junk-dna-induced-cancers-discovered/
http://www.evolutionnews.org/2010/10/micrornas–once_dismissed_as_j038861.html
Thank-you Ritu for emphasizing this important finding from the Guo paper.
Dr. Ritu,
Thank you for this post, much in keeping with our Thrust on the Link between ENCODE and Disease genetic origin discovery and follow up to therateupics used in management of Disease.
May I suggest to use this post as a linchpin to a post on its own right on ncRNA and Cancer sequencing results as in ENCODE publications.
This post pioneers a style of authorship I wish to encourage on our Scientific Web Site. Continuation of a peer’s research, linking concepts to additional cell types and other disease fields.
Great work paving a new road under construction.
Dr. Ritu,
You have really put lots of useful information about miRNA along with their links. Thanks!!! Expecting lots of post like this from you.
Meg, I enjoyed reading your post and have tried to emphasize the importance of miRs based disease treatment in this commentary.
Aviva, thanks for your input on the post. There is so much literature regarding miRs and their functions, therapeutic angle of miRNAs could now be explored. The literature on ‘ncRNA and Cancer’ would definitely be a great curated post.
Abhay, I am glad you liked my post and thanks for the encouragement. I would keep posting about different topics including mitochondria, Cancer, nitric oxide, bone research and so on. There are a lot of interesting posts you might come across in the blog.
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