A Computational Approach for the Identification of Novel L1 Transcriptional Regulators

Long interspersed element 1 (L1) are a family of autonomous, actively mobile transposons that occupy ~17% of the human genome. Though normally repressed by host cells, L1 expression and/or transposition frequency increase with age and in age-related conditions like cancer. When mis-regulated, its effects on host cells can be multipronged, driving genome instability, promoting inflammation, or facilitating mitochondrial dysfunction. Thus, it is imperative that hosts maintain precise regulation over L1. Though cell culture-based screens have been carried out to identify genes responsible for L1 transcription and transposition control, these catalogues are incomplete because of cell-type specific regulatory mechanisms. Here, we computationally identify candidate genes involved in L1 transcriptional control in lymphoblastoid cell lines (LCLs) and functionally characterize the impact of top candidates on L1 expression. Our results expand the catalogue of genes implicated in L1 transcriptional control and further highlight the importance of studying transposon regulatory mechanisms across cell types. Moreover, our study suggests that transposon eQTLs may be employed to search for candidate regulators in silico and in a high-throughput manner. Given the ever-increasing availability of paired genomic and transcriptomic data, we anticipate our approach to be a starting point for more comprehensive computational scans for transposon transcriptional regulators. For example, regulatory mechanisms could be characterized for other transposons, in other cell types, in tissues like those in the Genotype-Tissue Expression (GTEx) project, and among individuals with diverse genetic ancestries.