You Are What You Eat?!

Diet has long been known to alter gene expression.1 These alterations were previously thought to only depend on the genome of the mammal consuming the food. Any differences in gene expression were though to only depend on genetic variation in the consumer population. However, recent research has discovered a direct route for the plant genome to interact with the mammalian genome via epigenetic mechanisms.2 Ultimately, this cross-kingdom interaction holds great potential for understanding inherited molecular variation.

Changes in gene expression across cells are accomplished by a number of cellular communication mechanisms including microvesicles (MVs). MVs are small vesicles that are shed by almost all cell types under normal and pathological conditions. 3 MVs are known to selectively interact with target cells and mediate intercellular communication. The intercellular communication is carried out by the transport of bioactive lipids, mRNA, and protein between cells. MVs have recently been shown to contain miRNAs.4, 5 miRNAs are small, noncoding RNA molecules that mediate post transcriptional silencing and affect ~30% of protein coding genes.6 miRNAs are known to regulate critical biological processes and alterations in miRNAs are linked to disease.7 Zhang et al. have shown that endogenous miRNAs are present in human plasma where miRNAs can be selectively packaged into MVs and actively delivered into recipient cells. Intriguingly, Zhang et al. established that exogenous miRNAs act in a manner similar to endogoneous miRNAs in that they both can regulate gene expression and cell function. Through the aforementioned research, Zhang et al.  have shown that exogenous miRNAs are packaged into MVs and provide a novel method for intercellular communication.

In their latest research, Zhang et al. expanded on their previous work by discovering a novel cross-kingdom interaction between plant (rice) miRNAs and the mammals (humans, mice, and calves) that have consumed the plant miRNAs.2 Three important aspects of the cross-kingdom interaction were examined. First, the research showed that plant miRNAs are present in mammalian serum and MV’s. Second, the research showed plant miRNAs in mammals are of plant origin.  Third, the research showed plant miRNAs consumed by mammals are capable of altering mammalian gene and protein expression. Zhang et al. established the three important aspects of the cross-kingdom interaction by observing that rice mir-168a is capable of reducing LDLRAP1 transcript levels. LDLRAP1 is a receptor for Low Density Lipoprotein (LDL), also known as “bad cholesterol”, and  is responsible for removing LDL particles from the circulatory system. Zhang et al. fed mice mir-168a, which was associated with a down-regulation of LDLRAP1, and increased LDL levels. Additionally, the authors observed that consumption of mammalian miRNA has a similar affect on its target gene. The discovery of the cross-kingdom interaction creates a world of possibilities in the understanding of mammalian and plant genetics.

The cross-kingdom interaction sheds new light on the intimate association between mammals and plants at the level of inherited molecular variation. The potential for variation lies in the fact that plants encode thousands of miRNAs with only six nucleotides of perfect complementary being sufficient to promote RNA silencing in mammals. 8, 9 Furthermore, miRNAs can act as switch and fine-tuner of gene expression. 6 An individual miRNA may also have up to a few hundred different target mRNAs. 10 The properties of miRNAs suggest that plant miRNAs have the potential to regulate many genes in mammals. If allelic variants were found in plant miRNAs and/or their target mammalian genes, it would suggest the possibility of co-evolution between local plant and mammalian populations. If co-evolution were to occur, it would create the possibility of regional “epigenetic linkage units” in which an allele for a plant miRNA may be “epigenetically linked” to an allele of a mammalian target gene. Indeed, one can imagine humans caring for a plant population that provides a benefit. Mammals would be indirectly receiving epigenetic information through the environment and thus “inherit” different alleles from plants through the local environment. This process of “inheritance” is similar in principle to horizontal gene transfer; the main difference being that the transfer would be indirect as it occurs through the environment. In other words, the cross-kingdom effect could create regional biological systems where the plant miRNAs parallel as “plasmids” to the mammalian genome, and the environment parallels the “cytoplasm”. Regional biological systems would then be created where plant and mammalian members with mutually beneficial alleles form an “epigenetic linkage unit” with a regional fitness advantage. The biological system would blur the lines between genetics and environment, which is a common theme to epigenetic phenomenon. The cross-kingdom interaction would then have the potential to drive evolutionary forces. Therefore, the cross-kingdom interaction brings about a paradigm shift in our understanding of inherited molecular variation, suggesting that inherited molecular diversity is shaped by the interplay between regional mammalian and plant genomes. A greater understanding of the interplay between the mammalian and plant genomes will expand our knowledge on inherited molecular variation.

When interpreting the cross-kingdom interaction, one must not get carried away as there are many other environmental conditions to consider. Maternal behaviour and chemical exposure are amongst the wealth of environmental conditions known to modify gene expression via epigenetic mechanisms.11-13 Given the great amount of environmental “noise”, the cross-kingdom interaction must be examined to determine if it is of any significance amongst others factors or just “lost in the noise”. Only when the significance of the cross-kingdom interaction is established can it hold any ground to the understanding of inherited molecular variation as there must be a fitness advantage in order for the “epigenetic linkage units” to be selected for. Despite its limitations, the cross-kingdom interaction gives life to a potential paradigm shift and warrants further examination in the quest to better understand inherited molecular variation. Ultimately, you may find out that not only do your own genes determine what you are, but so do the genes of what you eat.

Figure 1

Plant and human populations in regional environmental/biological systems with distinct “epigenetic linkage units”. Colours in humans and plants are used to identify distinct alleles with the same colour between species indicating a beneficial interaction. Additionally, the colours in the regional environments indicate a cross-kingdom interaction that is best suited for that environment.

References

1. Wolff, G.L., Kodell, R.L., Moore, S.R., Cooney, C.A. (1998). Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J. 12, 949-957.

2. Zhang, L., Hou, D., Chen, X., Li, D., Zhu, L., Zhang, Y., Li, J., Bian, Z., Liang, X., Cai, X. et al. (2011). Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA. Cell Res.

3. Denzer, K., van Eijk, M., Kleijmeer, M.J., Jakobson, E., de Groot, C., Geuze, H.J. (2000). Follicular dendritic cells carry MHC class II-expressing microvesicles at their surface. J. Immunol. 165, 1259-1265.

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

5. Skog, J., Wurdinger, T., van Rijn, S., Meijer, D.H., Gainche, L., Sena-Esteves, M., Curry, W.T.,Jr, Carter, B.S., Krichevsky, A.M., Breakefield, X.O. (2008). Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10, 1470-1476.

6. Mukherji, S., Ebert, M.S., Zheng, G.X., Tsang, J.S., Sharp, P.A., van Oudenaarden, A. (2011). MicroRNAs can generate thresholds in target gene expression. Nat. Genet. 43, 854-859.

7. Zhang, Y., Liu, D., Chen, X., Li, J., Li, L., Bian, Z., Sun, F., Lu, J., Yin, Y., Cai, X. et al. (2010). Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol. Cell 39, 133-144.

8. Rajagopalan, R., Vaucheret, H., Trejo, J., Bartel, D.P. (2006). A diverse and evolutionarily fluid set of microRNAs in Arabidopsis thaliana. Genes Dev. 20, 3407-3425.

9. Lewis, B.P., Burge, C.B., Bartel, D.P. (2005). Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15-20.

10. Bartel, D.P. (2009). MicroRNAs: target recognition and regulatory functions. Cell 136, 215-233.

11. Anway, M.D., Cupp, A.S., Uzumcu, M., Skinner, M.K. (2005). Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308, 1466-1469.

12. Vandegehuchte, M.B., Lemiere, F., Vanhaecke, L., Vanden Berghe, W., Janssen, C.R. (2010). Direct and transgenerational impact on Daphnia magna of chemicals with a known effect on DNA methylation. Comp. Biochem. Physiol. C. Toxicol. Pharmacol. 151, 278-285.

13. Weaver, I.C.G., Cervoni, N., Champagne, F.A., D’Alessio, A.C., Sharma, S., Seckl, J.R., Dymov, S., Szyf, M., Meaney, M.J. (2004). Epigenetic programming by maternal behavior. Nat. Neurosci. 7, 847-854.

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