Abstract
Background: Owing to their transcription factor binding sites, endogenous retroviruses (ERVs) can act as cis-regulatory-elements (CREs). By invading genomes in waves, ERVs offer a substrate for lineage-specific adaptations but also, when dysregulated, for lineage-specific disorders. Their role as CREs in rapid placental evolution, and in the human-specific placental disorder preeclampsia, may thus provide a paradigmatic exemplar. Here then we systematically identify ERV-derived CREs controlling human placental gene expression with dysregulation in preeclampsia. Results: We identify 87 ERV-derived CREs located upstream of genes expressed in the placenta. A subset of nine, all belonging to the ERV3-MLT1/2 families and dating to the mouse–human common ancestor, are consistently dysregulated in trophoblasts from preeclampsia samples. Of the nine ERV3-MLT1-linked genes dysregulated in preeclampsia, five are novel candidates, while four were previously associated with preeclampsia, though their ERV-based regulation was not recognized. Focusing on EPS8L1, we predict enhancer activity of upstream MLT1(G1) and validate using reporter assay and genome editing. This vertebrate-specific gene is expressed in progenitor cytotrophoblasts and syncytiotrophoblasts and is overexpressed in preeclampsia, correlating with preeclampsia biomarkers and is not elevated in related pregnancy disorders. A soluble form of EPS8L1 is detectable in maternal plasma as early as between 24 weeks of gestation. EPS8L1 knockout in trophoblast in vitro is lethal, and its overexpression alters trophoblast behaviors characteristic of preeclampsia. Conclusions: We conclude that ERV3-MLT1functions as a trophoblast-specific CRE for several human genes and may be dysregulated in preeclampsia. As EPS8L1 has a form in maternal circulation, it may have utility in diagnostics.
| Original language | English |
|---|---|
| Article number | 364 |
| Number of pages | 31 |
| Journal | Genome Biology |
| Volume | 26 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 5 Nov 2025 |
Data Availability Statement
All data are available in the main text or the supplementary materials. New gene expression data generated for this paper is deposited into GEO under accession number: GSE263305 [45]. The bisulfite sequencing data of the MLT1F2-2 element upstream of CYP11A1 is available at [76]. ERV-derived enhancer prediction was deposited to https://github.com/amitpande74/human-transposons-enhancer-predicition and https://doi.org/10.5281/zenodo.16022218 [43, 44]. Full versions of gels, IF or IHC images are available at https://doi.org/10.6084/m9.figshare.29738765 [75]. Third party data utilized in the study are listed in Additional File 14.Acknowledgements
We gratefully acknowledge Professor Jenny Myers (University of Manchester) for providing us with samples fromthe Manchester cohort, which significantly contributed to this research.We sincerely thank Prof. Dr. Dominik N. Müller
for his valuable insights throughout the study and Dr. Julianna Zadora for her guidance and technical expertise. We also
thank Juliane Ulrich, Jana Czychi (Müller/Dechend Lab at Charite/MDC), T. Andreas and E. Kittmann (Blois’s Lab at UKE) for
their excellent technical assistance in generating this work.
Funding
Open Access funding enabled and organized by Projekt DEAL. R.A supported by National University of Sciences and Technology (NUST) Faculty development program, Islamabad, Pakistan. This work was also supported by grants from the Deutsche Forschungsgemeinschaft (DFG) HE 6249/5–1 to F.H.; BL1115/4–1 and BL1115/8–1, Heisenberg Program (BL1115/3–1, BL1115/7–1, and BL1115/11–1) to S.M.B, DE631/15–1 to R.D.; GE2223/2–1, GE2223/6–1 to A.G. and Heike Wolfgang Mühlbauer Stiftung to S.M.B; Y.X. was supported by China Scholarship Council (CSC) Program.
ASJC Scopus subject areas
- Ecology, Evolution, Behavior and Systematics
- Genetics
- Cell Biology