Computational modeling of RNase, antisense ORF0 RNA, and intracellular compartmentation and their impact on the life cycle of the line retrotransposon

Nearly half of the human genome is occupied by repetitive sequences of ancient virus-like genetic elements. The largest class, comprising 17% of the genome, belong to the type 1 Long INterspersed Elements (LINE-1) and are the only class capable of autonomous propagation in the genome. When epigenetic silencing mechanisms of LINE-1 fail, the proteins encoded by LINE-1 engage in reverse transcription to make new copies of their own or other DNAs that are pasted back into the genome. To elucidate how LINE-1 is dysregulated as a result of carcinogen exposure, we developed a computational model of key elements in the LINE-1 lifecycle, namely, the role of cytosolic ribonuclease (RNase), RNA interference (RNAi) by the antisense ORF0 RNA, and sequestration of LINE-1 products into stress granules and multivesicular structures. The model showed that when carcinogen exposure is represented as either a sudden increase in LINE-1 mRNA count, or as an increase in mRNA transcription rate, the retrotransposon copy number exhibits a distinct threshold behavior above which LINE-1 enters a positive feedback loop that allows the cDNA copy number to grow exponentially. We also found that most of the LINE-1 RNA was degraded via the RNAase pathway and that neither ORF0 RNAi, nor the sequestration of LINE-1 products into granules and multivesicular structures, played a significant role in regulating the retrotransposon's life cycle. Several aspects of the prediction agree with experimental results and indicate that the model has significant potential to inform future experiments related to LINE-1 activation.