Laboratory for Retrotransposon Dynamics

Genomic alterations drive evolution but also pose a threat to genomic integrity, potentially leading to disease-associated genome variations. LINE-1 (L1) and Alu retrotransposons continue to mobilize within genomes via a "copy-and-paste" mechanism known as retrotransposition, causing genomic instability.

While retrotransposons have evolved within host genomes over millions of years, hosts have developed defense mechanisms to suppress their uncontrolled mobilization. However, the specific mechanisms underlying this host-retrotransposon arms race remain unclear. We discovered that the innate immune system, mediated primarily by type I interferons, establishes an extensive defense network that suppresses L1 (Luqman-Fatah A. et al., Nat Commun. 2023). Within this network, we identified human HERC5, an interferon-stimulated gene (ISG) product, as a key suppressor. Human HERC5 specifically suppresses L1 by interacting with ribosomes to inhibit L1 translation, thereby significantly reducing L1 protein levels (Nishimori K. et al., bioRxiv 2025). Intriguingly, while the evolutionarily related human HERC6 lacks this activity, mouse HERC6 possesses it, compensating for the absence of HERC5 in the mouse genome. This highlights the arms race as an ongoing and dynamic evolutionary struggle.

Unlike L1, which encodes its own reverse transcriptase (RT) to retrotranspose autonomously, the non-coding element Alu relies on L1 RT for mobilization. However, defense mechanisms against Alu remain largely unknown, primarily due to the lack of effective reporters to visualize its retrotransposition. To address this, we developed a novel Alu-EGFP reporter to monitor Alu mobilization as a fluorescent protein. Using this reporter, we conducted a genetic screen and successfully identified a distinct set of defense factors separate from those targeting L1.

By elucidating the full landscape of these retrotransposon suppressors, we aim to uncover the comprehensive evolutionary strategy: how hosts suppress retrotransposons while simultaneously harnessing their potential to drive evolution.