Wednesday, March 21, 2012

The plot thickens -- you are what you eat in more ways than one

Your genome on lettuce
Banish the thought that you've got complete control over expression of your own genes.  It turns out that what you eat is also a player.  A paper in the April issue of BioEssays, "Beyond nutrients: Food-derived microRNAs provide cross-kingdom regulation" (Jiang, Sang and Hong), reports that not only do we derive nutrients from food, but that food-derived micro RNAs can affect expression of our genes.  Yet another instance of inter-species cooperation.

Micro RNAs are a relatively recently discovered component of the genome that modulate gene expression.  They silence protein-coding genes by binding to transcribed mRNA and preventing its translation.  As Jiang et al. report, more than 15,000 miRNA loci have been found in 140 species, and are annotated in the miRBase database.  These are miRNAs found inside cells, but recently micro RNAs have been found in blood serum and plasma, urine, saliva and other body fluids.  While RNA is known to be easily degraded and rather fleeting, it seems that these circulating RNAs are highly stable, and resistant to the usual destructive elements; RNAses, and high or low pH or temperature.  And, say Jiang et al., these miRNAs seem to be highly correlated with disease, such as cancers and diabetes, and with tissue injury, which suggests they could be of use as biomarkers.

But, the paper only notes this in passing, primarily focusing on these miRNAs as signaling factors.
Despite numerous reports of the detection of secreted miRNAs, the exact mechanisms of how these miRNAs are transported and act as signaling molecules are not clear. They have been implicated in stem cell function, hematopoiesis, and immune regulation. Recently, several lines of evidence have suggested that miRNAs are selectively packaged into microvesicle (MV) compartments to function efficiently in mammalian cells. MVs are membrane-covered vesicles and can be released by various kinds of cells.
It may be that being packaged in MVs is what gives these miRNAs their stability, as they are sequestered from RNAses and so on.  And, the packaging process seems to be selective, as only specific types of miRNAs have been found packaged in this way.

Jiang et al. write that "cross-kingdom regulation through miRNA/double-stranded RNA (dsRNA) has been observed in many organisms and engineered systems."  And, it often alters gene expression in the host organism.  Examples include planaria or other parasitic nematodes, which can take exogenous double stranded RNA into their cells, as do insects when fed plants.
For example, when cotton bollworm larvae are fed on plant material expressing dsRNA targeting CYP6AE14, whose gene product helps the insect to counteract the deleterious cotton metabolite gossypol, the transcript level of this gene is decreased and causes larval growth retardation.
It has recently been demonstrated (and we have to take Jiang et al.'s word for it, because the paper by Zhang et al. is in Chinese, unreadable by us) that "mature single-stranded plant miRNAs are present in the serum and tissues of mammals that use plants such as rice as their food sources."  They verified that these are plant RNAs, and that they survived passage through the mouse gastrointestinal tract intact.
Moreover, the authors identified the low-density lipoprotein receptor adapter protein 1 (LDLRAP1) as a target for MIR168a, a plant miRNA that was present at a relatively high level in human sera. The presence of exogenous pre-MIR168a or mature MIR168a miRNA can significantly reduce LDLRAP1 protein level in culture. Furthermore, feeding mice with rice that produces MIR168a reduced the amount of LDLRAP1 protein in liver, which in turn resulted in an elevation of the LDL level in mouse plasma. Both the decrease of LDLRAP1 and the increase of LDL in plasma, however, could be blocked by the addition of an anti-MIR168a antisense oligonucleotide. These elegantly executed experiments not only confirm the role of circulating miRNAs in intercellular communication, but also suggest that miRNAs can transport and function in a cross-kingdom manner.
How miRNAs would survive digestion and be absorbed is a question but without simple answers.  The first issue has to do with how they survive digestion and absorption across the gut.  A second is why we haven't evolved means to detect and degrade them; after all, our immune system is very able to recognize foreign stuff.  Jiang et al. describe the possible conditions under which plant miRNAs can survive this passage, and we won't replicate it here.  Suffice it to say that they note that plant miRNAs are packaged differently from mammalian miRNAs, and that mammalian intestinal epithelial cells 'somehow' ingest plant miRNAs.  They wonder if there's a receptor or some such on the mammalian cell surface that might recognize plant miRNAs and pave the way.  After being taken up by intestinal cells, these miRNAs then are passed to downstream cells, such as the liver, where they are involved in gene regulation.

There's a lot of hand waving going on here, but if true, this is a thought-provoking example of the synergy between organisms.  As this field matures, you can be sure that potential medical uses won't escape pharmaceutical companies.  

Regular readers may notice that in describing these newly discovered miRNAs, we've invoked a number of principles that we think are at the core of life, and that we've recently enumerated on MT -- sequestration, modularity, cooperation, signaling, chance, adaptability.  It's always gratifying when these principles apply in circumstances that were not known at the time we compiled them. 

Whose genome is it, anyway?
But what about evolution?  If we interact with genes (miRNA are coded from the originating species' DNA) from other species, and in at least many cases we depend on that, then perhaps the view of genomes as all contained within a species' cells is misleading.  Perhaps 'our' genome includes that of E. Coli that we need in our gut, or in each location 'our' genome includes miRNAs from foods we depend on for survival.

Normally, one would expect us to lose genetic mechanisms if they are replaced by something else.  If we depend on exogenous genetic information, then mutations in our own genes that do the same thing would have no selective disadvantage and would disappear.  In that sense, the species' genome becomes joined at the proverbial hip to each other.

Far-fetched?  Well, long ago mitochondria and chloroplasts entered cells and evolved from parasite to necessary cellular components.  miRNA and bacterial genomes and so on aren't so thoroughly incorporated (yet), though some viral genomes are.  So there is probably a gradient of intergenomic dependency among species.  This is an extension of predator-prey dependencies, but is similar in concept, just more localized in genes.

Once again, this discovery (if confirmed and shown to be more than trivial) will add to the causal complexity of human traits.


Holly Dunsworth said...

This makes me wonder about those sorts of dietary beliefs that take into consideration the live organisms' traits and behaviors. If their regulators can regulate your DNA, then there's a chance you can express like they do (as long as you have the right DNA). I haven't had enough coffee yet to provide a real example so I'll make two up: Like, you should eat a bull or a rooster if you want to win a fight later. You should eat a good hunter if you want to have a good hunt. Or you should avoid eating animals that are good at putting on fat if you're trying to win a battle with your weight. I might regret posting this half-baked comment, but I can't help it right now: I ate a half-baked muffin for breakfast.

Ken Weiss said...

If there is a safe message in this, it is (again) to temper our confidence with which we declare or hint at (or lobby for) the idea that we understand causation if we can just do some bigger studies (like big biobanks, whole genome sequencing, etc.).

A more focused response to the problems of causal prediction, especially these days in genomic terms, based on acknowledging how much we don't know and how complex things are, seems to me to be warranted.

But it's becoming less clear even what the causal questions are! If we evolved to eat plants to make us better hunters so we could eat wildebeests, then when we strode into Europe, did we have to rely on table scraps until we started eating some plant food that grew there and could help us go after elks?

Kurt Gielen said...

Hilarious! You should go and write for "The Big Bang Theory", they can use these kinds of jokes.
Thanks for this great laugh on a Monday morning.

Holly Dunsworth said...

Thanks Kurt! Confirms why people have told me that I need to watch that show!

Anonymous said...

I am late to this party, as I only just got around to reading the full text, but what I find most interesting about the Jiang paper is how they continue to refer to the interaction between organisms and their plant foods as "communication". For the most part, we usually think and speak in terms of "reacting" to components of our environment (including diet), but how often do we think about how it is *communicating* with us?

Hypothetical example:Let's say we are in a situation where food is not plentiful, and local produce is the only vegetable intake available. One day, a single carrot is our only veg intake. We pull the carrot out of the ground an eat it, but the carrot grew in soil that happened to be deficient in potassium.
From a "reaction" viewpoint- we eat that carrot and our body utilizes the potassium that we can get from it- maybe it's enough to fulfill our daily quota for K, maybe not. If not, the body's K homeostasis mechanisms will respond accordingly to increase K absorption or decrease K excretion.
From a "communication" viewpoint- we eat the carrot. There is the same type of reaction as described above, but, there's another type of signalling that occurs in addition. The carrot has produced certain miRNA molecules in response to growth in this deficient soil. These miRNA molecules originate to benefit the carrot, maybe by decreasing expression of certain genes involved in inhibiting uptake of K from the soil. When we eat the carrot, we absorb these miRNA molecules and they enter our circulation. We have evolved to recognize what these miRNA molecules represent, i.e. that there is a lack of K- *not only in this particular carrot, but also potentially in the immediate environment as well*, so certain genes involved in K homeostasis have evolved to include a target sequences for these miRNA molecules, such that expression of proteins involved in K excretion is decreased.
Thus, the miRNA from the carrot are acting as a message from the carrot, such that, in a way, it is essentially telling us about the environmental conditions it experienced during its growth; it is effectively, communicating with us.
To me this is a real shift in thinking about dietary influences and co-evolution...

Ken Weiss said...

A very good way to put things!

Holly Dunsworth said...

Agreed. Wow.