Functional characterization of enhancer activity during a long terminal repeat's evolution
- Alan Y. Du1,2,
- Xiaoyu Zhuo1,2,
- Vasavi Sundaram1,2,
- Nicholas O. Jensen1,3,4,
- Hemangi G. Chaudhari1,2,
- Nancy L. Saccone1,3,
- Barak A. Cohen1,2 and
- Ting Wang1,2
- 1Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
- 2The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
- 3Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri 63110, USA;
- 4Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
Abstract
Many transposable elements (TEs) contain transcription factor binding sites and are implicated as potential regulatory elements. However, TEs are rarely functionally tested for regulatory activity, which in turn limits our understanding of how TE regulatory activity has evolved. We systematically tested the human LTR18A subfamily for regulatory activity using massively parallel reporter assay (MPRA) and found AP-1- and CEBP-related binding motifs as drivers of enhancer activity. 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 owing to mutations in the AP-1 and CEBP motifs. We observed that the two motifs are conserved at higher rates than expected based on neutral evolution. Finally, we identified LTR18A elements as potential enhancers in the human genome, primarily in epithelial cells. Together, our results provide a model for the origin, evolution, and co-option of TE-derived regulatory elements.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.276863.122.
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Freely available online through the Genome Research Open Access option.
- Received April 25, 2022.
- Accepted August 23, 2022.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
