Transcending the one-locus-one-miRNA paradigm deepens the understanding of cancer biology and racial health disparities1
MiRNA isoforms (isomiRs) are molecules produced from a miRNA locus with variation at the 5’ or 3’ endpoints as compared to the “reference” or “archetype” miRNA. Previously, we had shown that the archtype miRNA is not necessarily the most abundant product and that the isomiR molecular profile is dependent on gender and race . In this new study , we extend our previous work in the breast cancer (BRCA) context and explore the characteristics and roles of isomiRs in BRCA molecular physiology.
The archetype miRNA is but one of several products that arise from one genomic locus. We find the distribution of products per locus to be skewed with as many as 43 isomiRs being produced from one locus. Importantly, the isomiRs are not “noise” but have functional importance as they improve the discrimination between normal and tumor samples and also between BRCA subtypes, as exemplified by the clear discrimination of the luminal A and luminal B subtypes. We also find that there are significant differences of the isomiR profile between triple negative BRCA tumors from white and African-American women, a BRCA subtype with known clinical differences between the two races. In all of the above comparisons, the archetype isomiRs were only part of the observed differences with the isomiRs significantly contributing to the observed molecular differences. When we explored the correlation patterns among isomiRs, we find that the endpoint choices and length of the isomiRs are much more important determinants than the genomic locus of origin. IsomiRs, similar to the archetype miRNAs, are loaded on Argonaute (Ago) but do so in a cell-type-dependent manner, as different BRCA model cell lines (corresponding to different BRCA molecular subtypes) exhibited distinct Ago-loaded profiles. To experimentally test the effect of isomiRs on the cellular transcriptome, we overexpressed the archetype miRNA of the miR-183-5p locus and two distinct isomiRs from the same locus and performed microarrays. We observed that the impact on the transcriptome was clearly distinct per isomiR.
These results argue for a much more complicated but important set of events at the post-transcriptional level. Precision/personalized medicine studies on gene expression and its regulation will therefore benefit from taking into account the full isomiR profile and go beyond the one-locus-one-miRNA paradigm.
- Telonis, AG, Loher, P, Jing, Y, Londin, E, Rigoutsos, I. Beyond the one-locus-one-miRNA paradigm: microRNA isoforms enable deeper insights into breast cancer heterogeneity. Nucleic Acids Res. 2015;43 (19):9158-75. doi: 10.1093/nar/gkv922. PubMed PMID:26400174 PubMed Central PMC4627084.
- Loher, P, Londin, ER, Rigoutsos, I. IsomiR expression profiles in human lymphoblastoid cell lines exhibit population and gender dependencies. Oncotarget. 2014;5 (18):8790-802. doi: 10.18632/oncotarget.2405. PubMed PMID:25229428 PubMed Central PMC4226722.