LINE-2 transposable elements are a source of functional human microRNAs and target sites

Transposable elements (TEs) are dynamically expressed at high levels in multiple human tissues, but the function of TE-derived transcripts remains largely unknown. In this study, we identify numerous TE-derived microRNAs (miRNAs) by conducting Argonaute2 RNA immunoprecipitation followed by small RNA sequencing (AGO2 RIP-seq) on human brain tissue. Many of these miRNAs originated from LINE-2 (L2) elements, which entered the human genome around 100-300 million years ago. L2-miRNAs derived from the 3' end of the L2 consensus sequence and thus shared very similar sequences, indicating that L2-miRNAs could target transcripts with L2s in their 3'UTR. In line with this, many protein-coding genes carried fragments of L2-derived sequences in their 3'UTR: these sequences served as target sites for L2-miRNAs. L2-miRNAs and their targets were generally ubiquitously expressed at low levels in multiple human tissues, suggesting a role for this network in buffering transcriptional levels of housekeeping genes. In addition, we also found evidence that this network is perturbed in glioblastoma. In summary, our findings uncover a TE-based post-transcriptional network that shapes transcriptional regulation in human cells. Author summary Transposable elements (TEs) are repetitive sequences, that have contributed to the landscaping of the genome by jumping into new positions and amplifying in number. TEs have been suggested to play a role in gene regulation, but it remains poorly understood how they contribute to this process. In this study, we show that in various human tissues, an ancient class of TEs give rise to small non-coding RNAs, called microRNAs (miRNAs), that are important regulators of gene expression. The same class of TEs also serves as target sites for these TE-derived miRNAs when they are part of protein-coding transcripts. We also provide evidence that TE-derived miRNAs and target sites may play a role in human disease, as they are dysregulated in aggressive brain tumors. Altogether, our study provides novel insight into how TEs acting as miRNAs play a role in gene regulation in both, healthy and diseased human tissues.