Much like the early explorers who set out to find a new trade route to Asia and accidentally stumbled across the Americas, researchers mapping the transcriptome have come across some big surprises. Recently, Isidore Rigoutsos’s lab showed that the expression of microRNA isoforms (called ‘isomiRs’) and tRNAs depends on sex, population, and race. Now, this talented team of transcriptome cartographers is at it again, identifying yet more diversity in the expression pattern of isomiRs that could help to classify breast cancer subtypes.
MicroRNAs help to regulate gene expression and are dysregulated in many diseases. It was thought that each microRNA existed in one form, but proving once again that the terrain of the transcriptome should never be underestimated, they are now known to exist as different isoforms, or ‘isomiRs’, with slightly different 5’ and/or 3’ termini.
We previously found that the expression of isomiRs differed substantially in healthy populations”, says lead author Rigoutsos, “which suggested to us that studying their expression may be important for understanding complex diseases like cancer.”
To map the expression pattern of isomiRs in a disease context, Rigoutsos’s team collected RNA-seq data from 294 breast tumors and 22 samples of normal breast tissue from The Cancer Genome Atlas (TCGA) repository, catalogued the transcribed isomiRs, and analyzed them. Here’s what they found:
- The isomiRs exhibited incredible diversity, with an average of five isomiRs arising from each miRNA locus.
- The analysis of isomiRs distinguished between normal and healthy tissue.
- Additionally the isomiRs responsible for differentiating normal from diseased tissue in white women differed from those in black women, highlighting the dependence of isomiR expression on race.
- The analysis of isomiRs also distinguished between major breast cancer subtypes.
Through follow-up experimental work the team also found that IsomiRs from the same miRNA locus can have very different targets. They transfected breast cancer cells with isomiRs of miR-183-5p, which are up-regulated in white but not black triple negative breast cancer patients, and analyzed gene expression by microarray.
Overlap between the genes that showed differential abundance in each case was only around 15%.
In Rigoutsos’s words, “It appears that going forward, it may not be sufficient to mention which microRNA one is studying. Instead, we might be compelled to state which specific isoform, in which cell type, and in patients of which race, gender, or population”.
Check out the most recent updates to the map of the transcriptome at Nucleic Acids Research, September 2015.