Question

Does anyone here know about the microRNA miR168? How would the microRNA function in its normal pathway?

Answer 1

ok ill throw in some context...
my anthropology professor posted this article http://www.livescience.com/16137-plants-animals-microrna-genes.html

Her conclusion was that being vegetarian may be detrimental to ones health. I disagree. The Japanese have one of the healthiest diets imaginable. But rice as the article mentions is a staple food in the Japanese diet. With the recent westernization of the Japanese diet the Japanese people have seen a sharp increase in the incidence of heart disease (my father being one of these people as he was raised in the US) http://eurheartjsupp.oxfordjournals.org/content/6/suppl_A/A8.full.pdf.
I do know that in plants miR168 can act as a co-regulator of mRNA in plants. http://www.ncbi.nlm.nih.gov/pubmed/16600876
I have also read that microRNA's in plants are very closely matched to their targets but in other organisms they are not as tight a fit. It seems that the microRNA when ingested does not indiscriminately bind with mRNA that it targets a certain LDLRAP1 producing mRNA....Why? I also read somewhere that microRNA's are highly conserved in eukaryotes I'm only guessing that this plays a part in the microRNA's ability to target our mRNA.

I have only taken a first year college level bio course so my understanding is somewhat limited but I would love to learn anything I possibly can about how microRNA's function. So if anyone could explain any part of what I just posted I would appreciate the information.

Answer 2

First of all, I am sorry that it took me 4 days for me to catch up with this one. I try to keep an eye on the OCW Biology group; I have been aware of the question but have had a crazy week and have not had time to do it justice. Excuses, excuses, excuses.

Secondly, it is a wonderful question. There are two parts to it and I will deal with them separately: the vegetarianism and the miR168 part.

I think it is either ignorant or irresponsible of your anthropology professor to post that article and from it argue that vegetarianism may be detrimental to one's health. The original article (not the one she posted, the one the researchers reported their findings in) merely reported the presence of plant derived RNA molecules; it did not look at whether the RNA molecules had any biologic effect at all, let alone whether the putative biologic effects are beneficial or detrimental.

The science behind it it is that many, many compounds and molecules from our diets have significant biologic effects (both good and bad) on our cells. Most research to date has focused on hormones - the two examples which come first to my mind are the estrogen in soy (yes, all that tofu vegetarians eat) has been associated both with lower incidences and better prognoses in breast cancer in women and lower incidences and slower progression of age-related dementia, especially Alzheimer's disease and all the artificial growth hormones inducing early puberty in girls who consume a lot of it. The authors of this study merely observe and confirm that the same uptake holds true for some RNA molecules as well as other classes of molecule.

If your professor had done a pubmed search on the health effects of vegetarianism, she would have found both that general studies looking at long term survival curves, morbidity and mortality among vegetarians is much lower than in omnivorous humans - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2677008/?tool=pubmed - and a substantial corpus of work teasing out the individual mechanisms in specific diseases which I am not got to cite here but which is readily accessible online.

You are free to link her to this post.

Answer 3

I meant "all the artificial growth hormones in milk" in that appalling run on sentence.

Answer 4

And now for the more scientifically interesting question about what the miR168 and Argonaute.

This is all about feedback mechanisms.

In general, microRNAs are a negative feedback mechanism. They are small snippets of RNA which bind through base pairing to specific target mRNA molecules and those mRNAs - now double stranded in regions - are then degraded. So when a cell wants to clean out mRNAs which it does not need anymore, it transcribes the appropriate microRNAs; the microRNAs bind the mRNAs and the whole complex is reduced to its individual nucleotides.

I should make it very clear that this discussion distinguishes between mRNA levels and levels of their actual protein products. Translation rates of different mRNAs vary but in general, the copy number of each mRNA
determines the rate at which cells can make individual proteins. They should not be confused with actual protein numbers within the cell.

Most known microRNAs come from longer precursor molecules and are activated - become able to bind their target mRNAs - by cleavage by a protein complex of which a protein called Argonaute (one of molecular biology's wonderfully named proteins) is the active component. It turns out that the levels of Argonaute mRNA is regulated by a microRNA, the miR168 that this study focuses on.

It is helpful to draw out the pathway on a piece of paper. It looks something like this:

So more miR168 --> higher degradation rate of Argonaute mRNA --> lower translation rate (and ability to quickly modulate translation rate) of Argonaute protein --> lower levels of Argonaute protein --> less synthesis of all microRNAs from precursor molecules --> less overall mRNA degradation.

The surprising thing that Vaucheret and Mallory found in the article you linked is that the miR168 precursor and the gene for the Argonaute protein are coregulated. When miR168 is transcribed so is its mRNA target! (That deserve an exclamation mark).

Why would a cell try to do two conflicting things at once? I do not speculate; I hypothesize.

The general answer is probably that feedback - also called cellular regulatory mechanisms or circuitry - is very, very complicated and subtle. As a computational biologist, mathematically modelling pathways like this is a lot of what I do.

The specific answer is that co-regulating the ARGO mRNA and the miR168 which clears the ARGO mRNA imposes a very tight, absolute level of regulation on the amount of ARGO mRNA in the cell. That makes sense biologically: ARGO is an essential protein in the production of microRNAs which regulate the levels of all mRNA transcripts and it makes good sense for the cell to tightly control both the absolute level of ARGO proteins it has and the rate at which ARGO proteins can be made (by controlling the mRNA level).

I have a gut feeling that there is probably a positive feedback loop somewhere in the regulatory circuitry which is driving both ARGO and miR168 expression. Positive feedback loops are rare but form the supporting skeleton of most essential signalling and regulatory pathways: they are how the cells maintain base levels of flux through those essential pathways and they always have this kind of tight control on the product end. The researchers working on this are probably working on that idea as we speak.

Hopefully that was helpful.

Answer 5

Hi Blues thank you so much for your very in-depth answer to my question. I just wanted to let you know that i'm sure I have a few more questions but its going to take me a few days to form up a real reply.

Answer 6

While, I did not really read all you wrote, I have a feeling that it has to do with miRNA from a plant affecting us? However, our spit and digestive system are loaded with RNase and DNase, I don't think any structured RNAs could get through.

Also, don't have time to read what you wrote, but please relevant: the book Super Immunity or Eat to Live by J. Fuhrman M.D.. He is a nutritionist, researcher, and his claims have many primary literature sources. He has treated and cured thousands of patients (documented) of diseases ranging from cancer to diabetes, and with the same method. Cut out processed foods, and eat a variety of high micro nutrient rich foods, the top of the list being green cruciferous vegetables.