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A distant trophoblast-specific enhancer controls HLA-G expression at the maternal–fetal interface
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A distant trophoblast-specific enhancer controls HLA-G expression at the maternal–fetal interface
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Journal Article
A distant trophoblast-specific enhancer controls HLA-G expression at the maternal–fetal interface
2016
Overview
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.
Publisher
National Academy of Sciences
Subject
/ Cells
/ Enhancer Elements, Genetic - genetics
/ Enhancer Elements, Genetic - immunology
/ Female
/ Gene Expression Regulation, Developmental - genetics
/ Gene Expression Regulation, Developmental - immunology
/ Histocompatibility, Maternal-Fetal - genetics
/ Histocompatibility, Maternal-Fetal - immunology
/ Humans
/ Immunogenetic Phenomena - genetics
/ Maternal-Fetal Exchange - genetics
/ Maternal-Fetal Exchange - immunology
/ Tissues
