The monoallelic nature of imprinted genes renders them highly susceptible to genetic and epigenetic perturbations, potentially resulting in transformation and disease. Here we show, using parthenogenetic induced pluripotent stem cells, an imprinted transcript that serves as an antisense regulator of onco-miR-372-3 (named anti-miR-371-3). As miR-372-3 have been shown to have an oncogenic role in testicular germ cell tumours, we study the involvement of their antisense transcript in these cells. Our results suggest that hypermethylation, leading to loss-of-expression of the imprinted antisense transcript, contributes to tumorigenic transformation by affecting the downstream target LATS2. Finally, we provide evidence for a tumour suppressive role of anti-miR-371-3, as its overexpression in tumour cells results in cell growth arrest and apoptosis, and prevents tumour formation on injection into immunodeficient mice.
Bibliographical noteFunding Information:
We thank Professor Peter W. Andrews for kindly providing Tera1 cells, Professor Reuven Agami for his kind donation of miR-371-3-overexpression vector and D. Ronen for his technical assistance with in vivo experiments. We thank T. Bruck, O. Kopper, D. Ronen and U. Ben-David for critically reading the manuscript. This research was partially funded by the Israel Science Foundation–Morasha Foundation (Grant number 1252/12) and by the Centers of Excellence Legacy Heritage Biomedical Science Partnership (Grant number 1801/10).