Regulatory Transposable Elements in the Encyclopedia of DNA Elements

Abstract Transposable elements (TEs) make up about half of the human genome and many have the biochemical hallmarks of tissue- or cell type-specific cis -regulatory elements. While some TEs have been rigorously documented to contribute directly to host gene regulation, we still have a very partial view of their regulatory landscape. Leveraging Phase 4 ENCODE data, we carried out the most comprehensive study to date of TE contributions to the regulatory genome. Here we investigated the sequence origins of candidate cis -regulatory elements (cCREs), showing that ∼25% of human cCREs comprising 236,181 elements are derived from TEs. Human-mouse comparisons indicate that over 90% of TE-derived cCREs are lineage-specific, accounting for 8-36% of lineage-specific cCREs across cCRE types. Next, we found that cCRE-associated transcription factor (TF) binding motifs in TEs originated from TE ancestral sequences significantly more than expected in all TE classes except for SINEs. Using both cCRE and TF binding data, we discovered that TEs providing cCREs and TF binding sites are closer in genomic distance to non-TE sites compared to other TEs, suggesting that TE integration site influences their later co-option as regulatory elements. We show that TEs have promoted TF binding site turnover events since human-mouse divergence, accounting for 3-56% of turnover events across 30 TFs examined. Finally, we demonstrate that TE-derived cCREs share similar features with non-TE cCREs, including massively parallel reporter assay activity and GWAS variant enrichment. Overall, our results substantiate the notion that TEs have played an important role in shaping the human regulatory genome.