Update on miRNA Mode of Action

February 19, 2013 | by Nick Snead

miRNA dotplotMicroRNA (miRNA) research has been a hot topic for about the past 5 years. PubMed searches will show papers from researcher(s) who have (apparently) found some miRNA that is involved in every minute process of the cell.

I have some personal impressions about miRNA research and results (which might anger some people?), as well as an update on their apparent mode of action.

For how many years have we seen some high-impact journal identify a single protein that appears to cause a disease? And how many times have people tried or even succeeded in drugging this protein target, only to find it doesn’t really give the efficacy they expected? My point is not that the research is flawed, or that the researchers didn’t have sincere intentions, or that they did not foresee some future technical challenges, but that the initial idea probably was too simplistic.

I hope that, as students at a cancer hospital and research institute, my colleagues have all been exposed to the fact that cancer arises due to massive aberrations in chromosomes, and/or severe dysregulation of multiple coding and non-coding RNAs and proteins. My view is that we need to continue to make progress in understanding functional versus dysfunctional gene networks. Hence, my interest in RNAi-based therapeutics, where sequence-specific suppression of virtually any protein coding genes can be targeted, particularly in a single formulation. (Run a Google search for Alnylam’s ALN-VSP clinical candidate, which targets both putative oncogenes, such as VEGF. But, I will not get on my soapbox about that.)

I think the same idea, that no single miRNA is a master regulator of any given process (except in very specific situations such as during development, where only a few cells of an embryo exist that have relatively few transcripts inside them and therefore are sensitive to slight perturbations) also applies. Despite some researchers wanting to believe that miRNAs can cause big changes, I feel the serious mechanistic miRNA researchers still submit that miRNA-mediated repression is weak (generally less than two-fold), and different miRNAs work as a team for subtle changes in protein production. Combining these two ideas together, we need to move past the oversimplified view of single miRNAs imparting major functions.

In late October 2012, I had a chance to hear a talk by David P. Bartel, Ph.D., a professor of biology at the Massachusetts Institute of Technology and member of the Whitehead Institute. He said that there are different views, due to a lingering belief based on previous research, about the way the levels of mRNAs that should be targeted by an miRNA do not change because miRNAs purportedly block translation without necessarily destabilizing (i.e., reducing the levels of) the mRNA. Dr. Bartel clarified in his lecture that blocking of translation without concomitant mRNA destabilization is detectable for only about 10 to 30 percent of miRNAs at early non-steady-state time points. But, for the other 70 to 90 percent of miRNAs at steady state conditions (which is when most of us do our experiments?), miRNAs destabilize their mRNA targets, which in turn leads to no protein being made from those mRNAs. So, for those of you doing miRNA/mRNA research, you should be seeing detectable mRNA reduction if your miRNA of interest is indeed targeting your mRNA in question.

After his talk, I asked Dr. Bartel, “What is the updated view on the idea that miRNAs are expressed when their targets are not (i.e., to catch leaky transcription)?”

To summarize his answer: When the mRNA is supposed to be present, there is a considerable amount of miRNAs to target it. But, when the mRNA is not supposed to be present, there is a lot of miRNA. He cautions, however, that the “catch leaky transcription” theory is not the main reason for this because miRNAs can only repress very small amounts. So, miRNAs probably don’t try to eliminate leaky transcription, just bring it down below a threshold where it is inconsequential.

I think he will agree that transcription factors are what drive most of the gene expression and repression.

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