Evaluating the cis-regulatory potential of full-length LINE-1 elements

Long interspersed element-1 (L1) retrotransposons constitute the largest transposable element (TE) family in mammalian genomes and contribute prominently to inter- and intra-individual genetic variation. Although most L1 elements are inactive, some evolutionary younger insertions remain intact and genetically competent for transcription and occasionally retrotransposition. Despite being generally more abundant in gene-poor regions, intact or full-length L1s (FL-L1) are also enriched around specific classes of genes and on the X chromosome. How proximal FL-L1 may affect nearby gene expression remains unclear. Here, we examine this systematically using engineered mouse embryonic stem cells (ESCs) in which expression of one active L1 subfamily is perturbed. We found that FL-L1 activation leads to the misregulation of ~1,024 genes, whereas FL-L1 repression affects ~81 genes. In most cases, misexpressed genes contain an intronic FL-L1 or lie near a FL-L1 (<260 kb). Gene ontology analysis shows that upon L1 activation, upregulated genes are enriched for neuronal function-related terms, suggesting that some L1 elements may have evolved to control neuronal gene networks. These results illustrate the cis-regulatory potential of FL-L1 elements and suggest a broader role for L1s than originally anticipated.