Tuesday, December 18, 2012

Plant miRNAs regulate human gene expression: believe it or not?

Plant miRNAs R us?
Just as we're starting to get used to the idea that our genomes include our microorganismal friends, who outnumber our own genes in our own bodies by a factor of 100, a paper that's not new but that has recently come to our attention, and may be new to you, too, suggests that we now have to make room for plants in this equation.  We blogged about a paper in BioEssays in the spring reporting micro RNA from plants regulating animal genes, but this second paper makes the story more interesting, in several ways.

The paper (Zhang et al.), published online in Cell Research a year ago, reports finding about 30 different plant miRNAs in human sera and tissues. They were surprised by this, and went on to explore a possible association between eating rice and the regulation of specific genes by micro RNA from that rice.  MicroRNAs (miRNAs) are 19-24 nucleotide pieces of non-coding RNA that mediate the regulation of about 30% of mammalian genes by silencing them, meaning that the proteins they code for are not made.

When this process was first discovered it was thought to be intrinsic to an organism's own gene regulation, and exclusively so, but foreign miRNAs have subsequently been found in human blood and tissues and have been seen to be potentially useful biomarkers for disease. From Zhang et al.:
miRNAs have been widely shown to modulate various critical biological processes, including differentiation, apoptosis, proliferation, the immune response, and the maintenance of cell and tissue identity. Dysregulation of miRNAs has been linked to cancer and other diseases. Recently, we and others found that mammalian miRNAs exist stably in the sera and plasma of humans and animals. Specific serum miRNA expression profiles show a great potential to serve as a novel class of biomarkers for the diagnosis of cancer and other diseases. Numerous reports have subsequently shown that unique expression patterns of circulating miRNAs reflect various physiological and pathological conditions.
The paper suggests that these extrinsically acquired miRNAs may play a role in disease as well.

Zhang et al. report that miRNAs can "pass through the GI tract of the mouse and enter the sera and organs." They suspected that the predominant miRNAs in human tissues were derived from rice, and thus must have been acquired through the diet. This is surprising, since RNA is generally quite unstable and easily degraded, and the GI tract is very acidic. The authors suggest that these miRNAs are protected from degradation by a form of chemical modification called methylation.

The researchers identified 50 human gene sequences that were perfect matches to one of the rice miRNAs they'd found in human sera. The most highly conserved such sequence is in the low-density lipoprotein receptor adapter protein 1 (LDLRAP1), a gene highly expressed in the liver and critical to the removal of ldl from the circulatory system. They determined with an in vitro assay determined that the miRNA was intact in liver cells, and that the level of LDLRAP1 protein was significantly decreased, while the LDLRAP1 mRNA was not affected, indicating that the miRNA was in fact silencing translation of the gene. This had the effect of keeping ldl levels high.

This is very interesting, and apparently the first demonstration of the possible effect of exogenous miRNAs on human health. It could be a demonstration of epigenetic effects on health, and gene by environment interaction, both of which seem to be significant players in human health, but only beginning to be understood. And it demonstrates surprising characteristics of RNA. If it is true it's a significant finding.

But then, if it's true, why didn't it appear in a major journal? Cell Research is a publication of the Nature Publishing Group in association with the Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), and calls itself the "leading research journal in China and the Asia-Pacific region." So, is it fair to suggest this significant of a finding should be published someplace else? The study got some play in the journal itself, discussed as a "Research Highlight, " e.g., and it has been cited 50 times to date, but primarily in lesser journals as well.  

Who believes what stories...and why?
This is an interesting example of the sociology of science.  The journal is not a mainstream Western journal, even if it is in collaboration with a major Western publisher, the authors are unknown to us, and the results are surprising, even though the researchers report what appear to be very careful and considered confirmation each step of the way (though they did need to publish a correction to an error in their figures in the next issue of the journal, which we actually find rather confusing, but that's another story).  This, at least for us, makes this work a bit difficult to interpret and accept.  That may seem unfair, but in fact this is how science should work -- replication of results, particularly if they are unlikely, may not constitute proof but it does make them more likely.

Another side of this is the social side of the politics of science in society.   The paper was the subject of some commentary when it appeared because of worry about genetically modified crops and their potential to interfere with gene regulation in the same way.  GM giant Monsanto saw fit to comment on the paper, saying essentially that very few plant miRNAs are found in human sera and tissues, and that the amount consumed would have to be much more than it is to have any effect. 

There are other reasons to oppose genetically modified crops (as there are reasons to think they are a great idea for a crowded planet).  The point here is that a study is seized upon by those whose point of view it supports, and there may be a tendency to accept it uncritically.  But people didn't seem skeptical about the results, which we find interesting.

On the other side of the coin, of course, is the possibility that the study didn't receive top billing because many research and commercial interests would be threatened by it.  So biased use of work goes both ways.

All we, who only know what we've seen in the story itself, can say is that if it's accurate, it really does deserve to be taken seriously.  It would challenge many notions of whose genome is whose, could give us another pathway for understanding health and disease, and it would surely present potentially important risks and issues about safety in us and/or in other agricultural or other human-associated species.

No comments: