Transposable elements (TEs) originate from ancient viral sequences integrated into the genome and have attracted increasing attention in recent decades after shedding their long-standing reputation as mere genomic parasites. Long non-coding RNAs (lncRNAs) are major effector molecules that coordinate genetic expression and various cellular processes and are strongly associated with TEs. In humans, 42% of lncRNA are thought to originate from TEs, and up to 83% of total lncRNAs contain at least one TE sequence. One fascinating aspect of TEs is their species-specific nature, which reflects their ancient origins and strong adaptation, a characteristic shared not only by lncRNA, but also immune genes and immune cells. The immune system, which has evolved through rapid adaptation, provides a useful context for analysing the neofunctionalization of TEs.
Among TE families, LINE-1 (Long Interspersed Nuclear Element-1) is unique as the only autonomous and most active TE in humans, with widespread genomic distribution. Our group has recently demonstrated that a LINE-1 element is critical for the biogenesis of a lncRNA that can modulate the immune response in vivo in mice by dampening inflammation. Following this breakthrough we aim to investigate the regulatory roles of LINE-1 elements and their encoded products in the context of human adaptive immunity. To this end, we have developed a CRISPR library targeting 25,000 LINE-1 loci in human immune cells. By repressing these elements in human lymphocytes, we anticipate uncovering novel lncRNA-associated regulatory pathways, cellular mechanisms, and potential therapeutic targets for immune modulation.