Science Update: Plant miRNA

Information storage and transfer are critical components of our modern connected world, but are just as essential to the natural world, too. Take, for example, the problem of antibiotic resistance: many bacteria have, in the course of the last seventy years, evolved the ability to defeat some of our most powerful germ-killing drugs.1 We’ve known for some time that part of how bacteria do this is by transferring key snippets of information back and forth, “sharing” antibiotic resistance across a global microbial network.2 This has allowed a much more rapid pace than predicted for the development of resistance, and it also highlights how little we know about cell-to-cell communication in nature.

In the realm of human disease and herbal therapeutics, we’ve uncovered many fascinating imbalances and mechanisms plants use to stabilize them. There are cell-surface receptors – many alkaloids, like those found in Belladonna or Ephedra seem to work that way.3 Other plant constituents, especially polyphenols such as those found in Curcuma, work on gene expression4—by unlocking or suppressing different sections of DNA, they help modulate the balance of inflammation, regeneration, birth and death in the human cell. Still others have the ability to interact with immune cells, perhaps through the effects of complex cocktails of polysaccharides and proteoglycans, helping to stoke the internal immune “fire” but also ensure that it doesn’t blaze out of control.5

There are many other mechanisms, some general, some more specific, that help us understand how plants work in the human body from a biochemical perspective. But as is the case with antibiotic resistance, our understanding of the information-sharing and processing systems of the natural world is still in its infancy. We are swimming in a soup of information every moment of every day and yet, like bored surfers on the internet, rarely take control of the channels we browse and the signals we let in. A case in point is the recent improvement in our understanding of microRNA—or miRNA for short—and how it impacts health and disease. This incredible class of molecules opens up a whole new field for therapeutics and may help explain some of the more subtle and mysterious ways plants work to balance our lives, but is rarely even mentioned among physicians and herbalists.

To understand miRNA, it’s worth taking a moment with the RNA molecule in general. Very similar to DNA, it can store information in the sequence of four “letters” on a chain. Using big RNA-based catalysts known as ribosomes, RNA takes genetic information and translates it into proteins, acting as a messenger between the instructions stored in DNA and the all-important enzymes and proteins that drive every process in our bodies. These strands are actually called “messenger” RNA (or mRNA for short, not to be confused with miRNA). For decades, biologists followed the rule that DNA is copied into mRNA, which then creates proteins in the ribosomes. Now we know that this apparent one-way flow of information is anything but one-way: proteins can affect what pieces of DNA are legible and which stay hidden, and even strands of mRNA can feed back on the DNA blueprint, altering how it’s read and copied.

miRNA, unlike mRNA, is usually a much smaller molecule (on the order of 20-25 “letters” on a chain, where mRNA can have over 2,000 on average.6  The first miRNA was discovered in 1993,7 and since then, researchers have identified thousands of different strands, in mammals, in humans, in plants—across the entire natural world. The function of miRNA is still somewhat unclear, though one common thread seems to emerge: these short strands are able to interact with other pieces of RNA, especially mRNA, by binding to them and (usually) inhibiting their effects. When you remember how crucial enzymes are to every process in our bodies, you can see how inhibiting certain strands of mRNA can have dramatic consequences: by binding to mRNA, miRNA can dramatically decrease the production of specific catalysts, shutting down key pieces of cellular activity.8 (Photo credit: Kelvinsong.)

Scientists started by observing miRNA in action in human and animal cells.  They quickly uncovered a whole range of fascinating effects—from basic housekeeping to keeping cancer at bay.9 Our blood is full of these important small molecules, and without them cellular processes lose an important way to fine-tune the production of catalysts and the regulation of day-to-day activity. As with most processes in nature, the activity of miRNA can be a double-edged sword: cancer cells, for example, begin to produce different miRNAs that can “infect” neighboring cells and contribute to the cancer’s survival, differentiation, and spread.10 Fascinatingly, miRNAs are also secreted in saliva and breastmilk11—implying that they can spread from individual to individual, too. Maybe we share some of the data-exchange systems that bacteria rely on, and can pass information back and forth between us.

But how are these miRNAs transferred? “Naked” RNA itself isn’t incredibly stable, especially in environments like the stomach, and it also doesn’t readily enter cells all by itself. It appears that most miRNA is packaged into little bubbles of fat—liposomes, or “exosomes” expelled from the cell. These exosomes are a shuttle for the miRNA, docking with neighboring cells to transfer their information payload,12 and also help protect them from different, hostile environments. The researchers who first identified these exosomes also discovered that the miRNA they contain is often not present inside the parent cell—implying that miRNA truly is a cell-to-cell signaling mechanism that helps knit together tissue behavior.

Until very recently, miRNAs were only thought to exist in animals. But in 2002, the first miRNA strand was discovered in a variety of Arabidopsis,13 and since then over 7,300 different botanical miRNAs have been identified from over 70 plant species.14 Chances are, all members of the kingdom Plantae produce miRNAs, just like animals do. Plant miRNA is slightly different from animal miRNA: in animals, native miRNA can affect many different messenger RNA strands with a lot of overlap in its activity, while plant miRNA is much more specific in its ability to bind animal RNA sequences. While the existence of botanical miRNA is interesting, and its affinity to our own RNA sequences intriguing, these ideas remained largely theoretical until 2012, when Lin Zhang and others discovered that miRNA from rice not only survived the human GI tract packaged into its exosomes, but that it entered the bloodstream and affected the production of an enzyme that removes cholesterol from our blood.15 This “evidence of cross-kingdom regulation by microRNA”, as Zhang put it, was groundbreaking. Since then, numerous studies have found further evidence that plants affect our genetic expression by delivering exosomes full of miRNA “information,"16 and researchers have found hundreds of different plant miRNAs in our bloodstream17—from rice, corn, soy, oats, tomatoes and red grapes, among others.

These days, we are finally starting to explore the therapeutic potential of botanical miRNAs and their probable roles in explaining how some traditional herbs work. One of my favorite examples is from the herb turmeric, Curcuma longa, the medicinal activity of which was long ascribed to polyphenols known as curcuminoids.18 These were found to work on inflammation, liver function, cancer and more in the human system – and naturally, high-potency curcuminoid isolates came into favor. But as recent research suggests that lower doses of whole-plant turmeric have similar effects to high-dose curcuminoids, many have begun to wonder why. The miRNA content of whole turmeric seems to have important abilities to affect all of the same processes affected by curcuminoids— especially the expression of pro-inflammatory genes.19 Similar research is finding targets in animals from miRNA in artichoke (Cynara scolymus),20 flax (Linum usitatissimum),21 red grapes (Vitis vinifera)22, and more23. Plants (and fungi—like reishi24 also seem to be able to regulate our own internal miRNA production, affecting chronic diseases like cancer and contributing to our understanding of how herbal medicines work.

In conclusion, the world of plant-to-human communication is expanding into new horizons with the discovery of cross-kingdom miRNA transfer. What is most fascinating to me is that all plants contain miRNA and can therefore participate in the fine-tuning of our cellular behavior, informing the production and activity of our critical internal catalysts. But unlike traditional phytochemicals, miRNAs are in every plant and use the same mechanisms of action – it’s just that each plant has a different story to tell, different information to share. miRNAs may encode what we as herbalists think of the plants’ “personalities” better than any isolated chemical might. And finally, we are starting to see that the food we eat isn’t just a source of raw materials and building blocks – it’s a crucial source of information about how to maintain balance in a changing environment. We are connected to, and driven by, plants in more ways than we understand. Undoubtedly, we will uncover more as we move forward. But for now, miRNA offers an exciting and practical way to understand how whole plants work.

1. Laxminarayan, Ramanan, et al. "Antibiotic resistance—the need for global solutions." The Lancet infectious diseases 13.12 (2013): 1057-1098.

2. Ochman, Howard, Jeffrey G. Lawrence, and Eduardo A. Groisman. "Lateral gene transfer and the nature of bacterial innovation." Nature 405.6784 (2000): 299-304.

3. Schmeller, T., et al. "Binding of tropane alkaloids to nicotinic and muscarinic acetylcholine receptors." Pharmazie 50.7 (1995): 493-495.

4. Kim, Ji H., et al. "Turmeric (Curcuma longa) inhibits inflammatory nuclear factor (NF)κB and NFκBregulated gene products and induces death receptors leading to suppressed proliferation, induced chemosensitization, and suppressed osteoclastogenesis." Molecular nutrition & food research56.3 (2012): 454-465.

5. Gao, Yihuai, et al. "Effects of Ganopoly®(A Ganoderma lucidum Polysaccharide Extract) on the Immune Functions in AdvancedStage Cancer Patients." Immunological investigations 32.3 (2003): 201-215.


7. R.C. Lee, R.L. Feinbaum, V. Ambros, The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14, Cell 75 (December (3)) (1993) 843–854.

8. D.P. Bartel, MicroRNAs: genomics, biogenesis, mechanism, and function, Cell 23 (2004) 281–297.

9. Calin, G. A., Dumitru, C. D., Shimizu, M., Bichi, R., Zupo, S., Noch, E., Aldler, H., Rattan, S., Keating, M., Rai, K., Rassenti, L., Kipps, T., Negrini, M., Bullrich, F., & Croce, C. M. (2002). Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 99, 15524–15529

10. Chen, X., Ba, Y., Ma, L., Cai, X., Yin, Y., Wang, K., Guo, J., Zhang, Y., Chen, J., Guo, X., Li, Q., Li, X., Wang, W., Wang, J., Jiang, X., Xiang, Y., Xu, C., Zheng, P., Zhang, J., Li, R., Zhang, H., Shang, X., Gong, T., Ning, G., Zen, K., & Zhang, C. Y. (2008). Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18, 997–1006.

11. Weber, Jessica A., et al. "The microRNA spectrum in 12 body fluids." Clinical chemistry 56.11 (2010): 1733-1741.

12. H. Valadi, K. Ekstrom, A. Bossios, M. Sjostrand, J.J. Lee, J.O. Lotvall, Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells, Nat. Cell Biol. 9 (2007) 654–659.

13. C. Llave, K.D. Kasschau, M.A. Rector, J.C. Carrington, Endogenous and silencing associated small RNAs in plants, Plant Cell 14 (2002) 1605–1619.

14. A. Kakrana, R. Hammond, P. Patel, M. Nakano, B.C. Meyers, sPARTA: a parallelized pipeline for integrated analysis of plant miRNA and cleaved mRNA data sets, including new miRNA target-identification software, Nucl. Acids Res. (2014).

15. Zhang, Lin, et al. "Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA." Cell research 22.1 (2012): 107-126.

16. M. Jiang, X. Sang, Z. Zhong, Beyond nutrients: food-derived microRNAs provide cross-kingdom regulation, Bioessays 34 (2012) 280–284.

17. K. Wang, H. Li, Y. Yuan, A. Etheridge, Y. Zhou, et al., The complex exogenous rna spectra in human plasma: an interface with human gut biota? PLoS One 7 (December (12)) (2012).

18. Akram, M., et al. "Curcuma longa and curcumin: a review article." Rom J Biol-Plant Biol 55.2 (2010): 65-70.

19. R. Rameshwari, D. Singhal, R. Narang, A. Maheshwari, T.V. Prasad, In silico prediction of mirna in Curcuma longa and their role in human metabolomics, Int. J. Adv. Biotechnol. Res. 2 (2013) 253–259.

20. P. De, D. aola, F. Cattonaro, D. Pignone, G. Sonnante, The miRNAome of globe artichoke: conserved and novel micro RNAs and target analysis, BMC Genomics 13 (2012) 41.

21. V.T. Barvkar, V.C. Pardeshi, S.M. Kale, S. Qiu, M. Rollins, R. Datla, et al., Genomewide identification and characterization of microRNA genes and their targets in flax (Linum usitatissimum): characterization of flax miRNA genes, Planta 237 (April (4)) (2013) 1149–1161.

22. S. Ju, J. Mu, T. Dokland, X. Zhuang, Q. Wang, H. Jiang, et al., Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from DSS-induced colitis, Mol. Ther. 21 (7) (2013) 1345–1357.

23. Sala-Cirtog, Maria, Catalin Marian, and Andrei Anghel. "New insights of medicinal plant therapeutic activity—The miRNA transfer." Biomedicine & Pharmacotherapy 74 (2015): 228-232.

24. Li, Aimei, et al. "Ganoderma lucidum polysaccharide extract inhibits hepatocellular carcinoma growth by downregulating regulatory T cells accumulation and function by inducing microRNA-125b." J Transl Med 13 (2015): 100.

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