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Updated: Aug 26, 2025
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Prediction and Validation of Gene Regulatory Elements Activated During Retinoic Acid Induced Embryonic Stem Cell Differentiation
Published on: June 21, 2016
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Functional characterization of enhancer activity during a long terminal repeat's evolution.
Alan Y Du1,2, Xiaoyu Zhuo1,2, Vasavi Sundaram1,2
1Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Genome Research
|October 3, 2022
Summary
Transposable elements (TEs) like LTR18A can act as gene regulators. This study shows they often lose regulatory function over time, particularly due to changes in AP-1 and CEBP binding motifs.
Area of Science:
- Genomics and Molecular Evolution
- Epigenetics and Gene Regulation
Background:
- Transposable elements (TEs) are mobile DNA sequences that can influence genome evolution.
- TEs often contain regulatory motifs, but their functional regulatory roles are frequently uncharacterized.
- Understanding the evolution of TE regulatory activity is crucial for deciphering their impact on host genomes.
Purpose of the Study:
- To systematically investigate the regulatory potential of the human LTR18A transposable element subfamily.
- To explore the evolutionary trajectory of TE regulatory activity and identify key sequence drivers.
- To determine the genomic locations and cell-type specificity of active LTR18A regulatory elements.
Main Methods:
- Massively parallel reporter assay (MPRA) was employed to functionally test LTR18A sequences for enhancer activity.
- Evolutionary reconstruction of ancestral LTR18A sequences was performed to analyze changes in regulatory function over time.
- Bioinformatic analyses were used to assess motif conservation and identify potential genomic enhancer sites.
Main Results:
- AP-1 and CEBP transcription factor binding motifs were identified as key drivers of LTR18A enhancer activity.
- Analysis of reconstructed ancestral sequences revealed a general loss of regulatory activity in LTR18A elements over evolutionary time.
- Mutations within AP-1 and CEBP motifs were found to be major contributors to this loss of function, with these motifs showing conserved rates higher than neutral evolution.
Conclusions:
- The human LTR18A subfamily possesses regulatory potential, primarily driven by AP-1 and CEBP motifs.
- LTR18A elements have evolved towards a loss of regulatory function, with significant contributions from sequence changes in key motifs.
- LTR18A elements function as enhancers in the human genome, particularly within epithelial cells, providing a model for TE-derived regulatory element evolution.
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