The potentials of isomiRs – a new dimension in biomarker research

Benedikt Kirchner, Ming Wu, Dominik Buschmann, Michael W. Pfaffl*,
Animal Physiology & Immunology, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany

Recent studies have proven that microvesicles are a valuable source of biomarkers in a number of physiological and pathophy- siological states. The molecular content of exosomes (and other vesicles) and their miRNA cargo in particular can act as a unique ‘biomarker signature’ and help identifying releasing cells and their circumstances.
While knowledge of the extensive target repertoire of individual miRNAs greatly expanded our understanding of miRNA functions, the high resolution down to single nucleotide alterations enabled by small-RNA sequencing technologies added an entire new layer of complexity by detecting a great abundance of miRNA isoforms. These isomiRs show significant sequence and length heterogeneity, generated by base exchanges from the canonical sequence, and/or additions and/or deletions at the 3′ or 5′ end. The quantified isomiRs can change the mRNA targeting behaviour, either subtly through supplementary or complementary binding at the 3′ end, or drasti- cally by altering the seed sequence at the 5′ end. By taking these target gene shifts into account and using a consensus of predicted genes that reflects actual miRNA sequence distribution and binding efficiencies, the accuracy of predicted pathways and related dis- eases is greatly improved. To realize this approach we implement these ideas in a ‘bioinformatical pipeline’ which analyses the small RNA sequencing read data files in a fully automatic way.
The assessment of mRNA targets can help discern the phys- iological relevance of identified miRNA biomarkers and even uncover novel relationships. We apply this ‘analysis pipeline’ to discover new integrative mRNA/miRNA regulation pattern in agri- veterinary research and to predict new ‘miR biomarker signatures’ in human clinical diagnostics.

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