ArticleProceedings of the National Academy of Sciences of the United States of America2016
A distant trophoblast-specific enhancer controls HLA-G expression at the maternal-fetal interface.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 93 citations in OpenAlex.
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- Immunomodulatory effect of mesenchymal stromal cell overexpressing HLA-G1 in cell-based therapy for myocardial infarction.Stem cell research & therapy · 2026Article
- Modulation of the PGRMC1/NLRP7/HLA-C axis by autophagy is linked to both spontaneous preterm birth and gestational choriocarcinoma.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- BHLHE40 Cooperates with GATA2/3 to Control Human Syncytiotrophoblast Lineage Differentiation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The Clinical Implications of Progesterone in Preeclampsia.Biomolecules · 2025Review
- Human Extravillous Trophoblasts Require SRC-2 for Sustained Viability, Migration, and Invasion.Cells · 2025Article
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- The TEA domain transcription factors TEAD1 and TEAD3 and WNT signaling determine HLA-G expression in human extravillous trophoblasts.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Harnessing the immunomodulatory properties of HLA-G for advanced immunotherapies.Frontiers in immunology · 2025Review
- HLA-C expression in extravillous trophoblasts is determined by an ELF3-NLRP2/NLRP7 regulatory axis.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Progesterone-mediated remodeling of the maternal-fetal interface by a PGRMC1-dependent mechanism.Journal of reproductive immunology · 2024Article
- Towards targeting transposable elements for cancer therapy.Nature reviews. Cancer · 2024Review
- Lower HLA-G levels in extravillous trophoblasts of human term placenta in gestational diabetes mellitus than in normal controls.Histochemistry and cell biology · 2023Article
- The Immunological Conundrum of Endogenous Retroelements.Annual review of immunology · 2023Review
- Essential role of an ERV-derived Env38 protein in adaptive humoral immunity against an exogenous SVCV infection in a zebrafish model.PLoS pathogens · 2023Article
- Translating non-coding genetic associations into a better understanding of immune-mediated disease.Disease models & mechanisms · 2023Review
- The embryo non-invasive pre-implantation diagnosis era: how far are we?Animal reproduction · 2023Article
- Regionally distinct trophoblast regulate barrier function and invasion in the human placenta.eLife · 2022Article
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
HLA-G, a nonclassical HLA molecule uniquely expressed in the placenta, is a central component of fetus-induced immune tolerance during pregnancy. The tissue-specific expression of HLA-G, however, remains poorly understood. Here, systematic interrogation of the HLA-G locus using massively parallel reporter assay (MPRA) uncovered a previously unidentified cis-regulatory element 12 kb upstream of HLA-G with enhancer activity, Enhancer L Strikingly, clustered regularly-interspaced short palindromic repeats (CRISPR)/Cas9-mediated deletion of this enhancer resulted in ablation of HLA-G expression in JEG3 cells and in primary human trophoblasts isolated from placenta. RNA-seq analysis demonstrated that Enhancer L specifically controls HLA-G expression. Moreover, DNase-seq and chromatin conformation capture (3C) defined Enhancer L as a cell type-specific enhancer that loops into the HLA-G promoter. Interestingly, MPRA-based saturation mutagenesis of Enhancer L identified motifs for transcription factors of the CEBP and GATA families essential for placentation. These factors associate with Enhancer L and regulate HLA-G expression. Our findings identify long-range chromatin looping mediated by core trophoblast transcription factors as the mechanism controlling tissue-specific HLA-G expression at the maternal-fetal interface. More broadly, these results establish the combination of MPRA and CRISPR/Cas9 deletion as a powerful strategy to investigate human immune gene regulation.
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