Factors Regulating Retrotransposon Expression : Uncovering a Novel BRCA1 Related Mechanism in Ovarian Cancer

Abstract

Retrotransposons constitute about a third of our genome. It is challenging to identify the causes and consequences of retrotransposon expression in human disease due to hundreds of active genomic copies and poor conservation across species. We profiled genomic insertions of retrotransposons in ovarian cancer. RNAs exhibiting Bayesian correlation with retrotransposon RNA were analyzed to identify potential causes and consequences of retrotransposon expression in ovarian and breast cancers. This strategy found divergent inflammatory responses associated with retrotransposon expression in ovarian and breast cancer. It identified new factors inducing the expression of endogenous retrotransposons, including anti-viral responses and the tumor suppressor BRCA1. In cell lines, mouse ovarian epithelial cells and patient-derived tumor spheroids, BRCA1 promoted the accumulation of retrotransposon RNA and facilitated transcription of active families of retrotransposons and their insertion into the genome. Intriguingly, elevated retrotransposon expression predicted survival in ovarian cancer patients. Retrotransposons are part of a complex regulatory network in ovarian cancer, including BRCA1 contributing to patient survival. The above-described analysis strategy could also be used to identify the regulators and impacts of retrotransposons in various contexts of biology and disease in humans.