Workshop Report 32

What are miRNAs?

Tim Gant, Head of Toxicology, Centre for Radiation, Chemical and Environmental Hazards, Public Health England (PHE) and University of Surrey, UK

MiRNAs regulate gene expression at the post-transcriptional level predominantly by mRNA degradation or the inhibition of mRNA translation by binding to the 3′-untranslated regions (3’-UTR) of specific mRNAs. Further, miRNAs appear to play a role in the transgenerational transmission of altered phenotypes through the male germ line. Compared with mRNAs, only a small number of miRNAs have been identified, i.e. 4552 unique human miRNAs (at the time of writing) as compared to 30,000 known human mRNAs. However, one miRNA may regulate the expression of many mRNAs (by partial complementary base pairing). Hence, even though miRNAs are smaller in number, their effects on the phenotype of the cells may be substantial (Hannon and Rossi, 2004). By controlling mRNA translation, miRNAs elicit effects on the cellular protein levels, and the more miRNA is present in the cell, the less protein will be translated (Selbach et al, 2008). MiRNAs may be tissue specific, e.g. miR-124 in the brain, miR-133a in the heart, or miR-122 in the liver, the latter being well explored in regard to drug overdose-induced hepatotoxicity (Laterza et al, 2009). Tissue-specific miRNAs may be relevant biomarkers for RA, even more so since they are stable and may be found in all body fluids. Finally, miRNA may play a role in the evolvement of chromosome aberrations (Calin and Croce, 2006).

In the human genome, the majority of miRNAs is located in between genes (i.e. they are intergenic), where miRNAs are organised into cistronic and polycistronic regions, i.e. expressing one or more miRNAs, respectively (He et al, 2005). Nevertheless, miRNAs may also be found in the introns of genes, whereby they are under the control of a mRNA promoter and enhancer region. Such miRNAs often act as feedback loops to the genes in which they are contained. Finally, the smallest group of miRNAs are exonic (Gant et al, 2015). During embryonic development, miRNAs may be involved in the very early stages of gene transcription that begins in zygotes during the eight-cell stage. If such gene transcription processes are disturbed, e.g. by environmental or epigenetic factors, there is the potential (currently hypothetical) for the phenotype of the resulting embryo to be affected (Trerotola et al, 2015).

In the search for ncRNA biomarkers, some priority should be given to the class of miRNA as their functions in terms of controlling gene expression in a wide variety of cellular processes (including proliferation, differentiation and development) and of involvement in both toxicity and disease is currently best understood. Furthermore, some miRNA exhibit organ-specific expression, and they can be detected in the blood plasma thereby acting as distant biomarkers of adverse events. This focus should not exclude other forms of ncRNAs, which will most likely assume an equal status as their roles in physiology and disease are better understood.

Q&A

Are changes in miRNA possibly molecular initiating events (MIE)? – This depends on the context: They could constitute a MIE, but they could also constitute downstream steps of an adverse outcome pathway (AOP; Ankley et al, 2010).

In respect to tissue-specific expression patterns of miRNAs, what are the (patho-)physiological implications of the high contents in body fluids? – This is not yet understood.

Will miRNA levels change over life stages of animals or humans? – Yes, and in response to changes in environment.