It has been extensively demonstrated that the expression pattern of microRNA is regulated spatio-temporarly and in function of biotic and abiotic factor. So far, a simple answer to your question would be: YES, microRNA may be diferentially regulated at the transcriptional level in different tissues. The mechanism to explain this regulation is where the complexity remains!

i think it doesn't remain the same

Hi Ashraf

Always good questions !... Transcriptions factors belong to many families, some of them are more promiscuous than others. So, I am afraid that the answer to your question is not easy. Specificity of a given miRNA in a particular tissue could be due to several different transcription factors.

Thanks Francisco,

I am really like lost when I came across this question. There are reports of transcriptional regulation of some microRNAs, e.g. I know about miR-143/145 and miR-223.

miR-223 is been shown to be regulated by C/EBP, NFI-A and PU.1 (http://www.sciencedirect.com/science/article/pii/S0092867405009773, http://www.sciencedirect.com/science/article/pii/S0092867407003947) in granulopoiesis system. Does that mean that the above mentioned transcription factors only control its regulation in other cell types as well? Or one will have to everytime study the regulation of mir-223 independently in different cell types to find which TFs are controlling its regulation?

It's possible, although it's not common because most miRNAs show differential expression in different organs. there are a couple of ways that can regulate miRNA expression, in some cases even frequency of target in a give tissue can regulate the miRNA expression. So, TFs are just one of those mechanisms and if a given miRNAs is regulated by a specific TF(s) in different cells, it doesn't mean that miRNA should have the same expression pattern everywhere.

its different in different tissue/organs/cells. It is possible that two microRNAs shows orthologous functions.

It has been extensively demonstrated that the expression pattern of microRNA is regulated spatio-temporarly and in function of biotic and abiotic factor. So far, a simple answer to your question would be: YES, microRNA may be diferentially regulated at the transcriptional level in different tissues. The mechanism to explain this regulation is where the complexity remains!

The question is very good and relevant. But it is not easy to answer in the light of current knowledge. We need more data and further explore the link between transcription factors and microRNAs. Recently we published an article (see below) in which we discuss this issue.

Macedo C et al (2012) Autoimmune regulator (Aire) controls the expression of microRNAs in medulary thymic epithelial cells. Immunobiology (in press, see it in PubMed).

Transciptional regulation in itself is dependent on factors stated by Rogerio, however I would presume that functions regulated by miRNA which are less likely to vary on grounds of such abiotic or biotic factors, say comparison drawn between miRNAs that affect telomere expansion rather than a bud/fruit formation will likely to remain constant throughout the entire system of animal/plants. The transcription profile of such miRNA affecting telomere specific expansion will need to show similar level's of regulation provided the cells of different tissues/organs taken for scrutiny pertain to the same level of differentiation, state of development cycle and time of monitoring the activity.

It all boils down to the energetics and limiting factors necessary to transcribe that miRNA to expend its function. If there are is a difference in the limiting factors, then transcription profile will be different. Say for example 2 cell lines of islet of pancreas of the same mother culture at the same development stage is grown on different levels of sugar concentrations, then a miRNA targeting glucose regulation will be directly affected and both cell lines are bound to produce difference in the transcription profiles. However, this is not an experimental data... it is a possible dependency on factors.

Mr Ashraf, I think you are now clear to get your answer from the above discussions. the very simple way to understand the answer to your question is that expression of miRNA is purely several signal molecule dependent which is again tissue specific in normal physiological conditions. Obviously then it will be organ specific. Even you expose an animal model to a same stress may be biotic or abiotic, then the expression level will be again tissue or organ specific to the same stress. It is purely due to the transcriptional or biological levels of the signal molecules involved in expression of miRNA.

1- miRNA expression is first controlled by TF

2- Then cellular level miRNA can by controlled by proteins in pathway like DGCR8, EXP5. These proteins are controlled for miRNA processing and nucleus-cytoplasm export.

3- each tissue has its own TF levels

4- Each time, there are different level of TF within the cell differentially

5- miRNAs regulate each other, too.

6- splicing has a great impact on miRNA generation

7- environmental factors affects the TF profile of the cells

8- Near-far cell:cell interactions through miRNAs affects

9- ...

Well, the answer could be No and Yes. No, because the expression of miRNA is cell/Tissue dependent as has been exhaustively documented. It seems logical in view of the diversity and intricacy of cell function.

Yes, may be under certain conditions [still unknown to scientists], a more global control exists.. Remains to be seen.

Do Visit this link:

http://www.nature.com/onc/journal/v31/n38/full/onc2011583a.html

Thanks everybody for contributing to this interesting discussion. This gives rise to another question, if microRNAs are expressed in every tissue they are observed or they are just expressed in one organ where they are enriched and then delivered to remaining tissues as per the requirement?

Your question needs a bit more description. In our culture, we say "good question is the half part of the answer". But what I know is that miRNAs are regulatory RNAs. They regulate gene expression in all levels including pre-transcriptional (epigenetics), transcriptional, post-transcriptional, translational and post-tra. They are detected in all tissues and cells which are studied. From embryonic cells to brain. They are recently found in 11 body fluids: blood, milk, urine, ...

This means that expressed miRNAs (spatio-temporarily) can regulate inter- and intracellular. They are packed and secreted to extracellular area and mediate the crosstalk of cell together. Interestingly, they regulate near and even far cells, specifically. This means that they use a cell-specific delivery system in our body.

But more interesting and most complicated issue is that how they are regulated? If you check publication, there are huge amount of papers challenging on especially in cancers.

@ Sadegh Jamalkandi: To elaborate my last question - lets say microRNA X is maximally expressed in the heart, but its expression is also observed in other organs (lets say 10 to 20 times lower than the heart). So is it that microRNA X is synthesized in all the above mentioned organs, or it is only expressed in the heart and then delivered to other tissues?

I know this is possible in some of the cases but I am not sure if it is true for all microRNAs. This microRNA story always looks myterious to me.. whatever I read, I always get more questions than answers. I mean it is just a 22 nucleotide fragment, but it can completely change the phenotype of the cell or would lead to or can prevent pathological conditions!!!

I think this is just the beginning and there is still a long way to go before we know all about microRNAs.

Dear Ashraf;

Both cases seem possible. miRNA X should be studied. miRNAs are regulators within a cell. In some cases, a especial miRNA works as a signaling molecule. It is secreted out and s delivered to a specific cell.

The interesting point is this: If miRNA X is taken by a target tissue or cell, what can it do? imagine 3-4 miRNAs entering into a cell. In plants these small RNAs are amplified by some mechanisms but in mamals its not been reported yet. So if you wan to check the celular origination of a miRNA, you hould check its pre-miRNA and pri-mRNA, first. If you could see them, you can say its not migrant miRNA. But if you couldn detect the pri-miRNA and pre-miRNA, you can quess that its a migrant miRNA.

@Sadegh Jamalkandi, is it possible that a specific miRNA is synthesized in one cell/tissue and transported to the other kind of cells/tissue, how?

Hi Ashraf Rangrez,

As far as I know the expression of the mi-Rnas depends much more on the pathological situation than the cell type. It means that for example, mi-R155 and 21 are expressed under inflamatory conditions in T cells and other inflammatory cells in the tissues where the inflammation is taking place. At the same time, other mi-RNAs which are antinflammatory, like mi-R146 , are expressed in those inflamatory cells in the same organs.

Dear Hamid Khan I suggest you read this paper in order to answer that question: http://bloodjournal.hematologylibrary.org/content/119/3/646.full

Hi Hamid Khan,

Mafalda Santos suggested u a very good paper which clearly explains ur question

@ Mafalda Santos & Shiek Ahmad Thanks alot for your suggestions. It really improved my knowledge but still confused with few things.

1) At one time a miRNA can do both functions ie targeting the mRNAs inside its own cell and at the same time in the other cell via exosome.

2) What are the factors that signal the miRNAs to be exported via exosomes and target a specific cell which also have the target mRNA.

3) Besides exosome mediated transfer, is there any other method for miRNA delivery to other cells?

@ Hamid Khan

miRNAs can function in cell-cell signaling process. Its demonstrated now. There is no doubt about it. But there are much questions about how these circulating miRNAs are released? Then how they are specifically delivered to the target cells. 3rd question is how single delivered miRNA can function within the recipient cells? These questions are under challenge. You will find many works trying to clarify the issue.

Exosomes are one of the carriers observed. LDL-loaded, Protein bound (Ago-bound miRNAs) are other cases along with apoptotic bodies. In fact very interesting issue but in its infancy research period.

This is a new horizon in RNA biology in which small RNAs are nominated as new multi-way cell-cell signaling strategies totally different from hormone-receptor or cytokines signaling. Scientists are trying to find out more about this mystified process to shed light on new drugs and also drug delivery systems. This is why there are huge investments in RNAi based drug developments by giant companies.

@Sadegh Jamalkandi ; thanks alot for detailed answer

Answer to Hamid's third question: base pairing?

@ Diane K. lavett; base pairing ? how? In my third question i have asked is there any other method (natural) of miRNA transfer from one cell to the other?

I think there is a misunderstanding about the original question. He is asking something else and others are talking about some else.

@ Vahid Vashar

Please reconsider the trend of questions. Topics is the first question which is followed by other questions. Isn't it?

@ Sadegh Jamalkandi

If first question is answered well, but not without enough discussing, opening new window ....