![]() Furthermore, redundant enhancers, or “shadow” enhancers, provide robustness in gene regulatory networks and may allow for greater freedom to develop new functions 5, 6. This modularity can minimize functional trade-offs and allows selection to act more efficiently 4. Enhancers are often active depending on cellular context like cell type or response to stimuli. Due to several unique properties, enhancers have emerged as excellent candidates upon which evolution can act. Since the discovery of the SV40 enhancer element, enhancers have emerged as one of the major classes of cis-regulatory sequences that can modulate gene expression 2, 3. Together, our results provide a model for the origin, evolution, and co-option of TE-derived regulatory elements.Ĭhanges in gene regulation have long been implicated as crucial drivers in evolution 1. Finally, we identified LTR18A elements as potential enhancers in the human genome, primarily in epithelial cells. We observed that the two motifs are conserved at higher rates than expected based on neutral evolution. Functional analysis of evolutionarily reconstructed ancestral sequences revealed that LTR18A elements have generally lost regulatory activity over time through sequence changes, with the largest effects occurring due to mutations in the AP-1 and C/EBP motifs. We systematically tested the human LTR18A subfamily for regulatory activity using massively parallel reporter assay (MPRA) and found AP-1 and C/EBP-related binding motifs as drivers of enhancer activity. However, TEs are rarely functionally tested for regulatory activity, which in turn limits our understanding of how TE regulatory activity has evolved. Many transposable elements (TEs) contain transcription factor binding sites and are implicated as potential regulatory elements.
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