A distant trophoblast-specific enhancer controls HLA-G expression at the maternal-fetal interface

68Citations
Citations of this article
147Readers
Mendeley users who have this article in their library.

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.

References Powered by Scopus

Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

35977Citations
N/AReaders
Get full text

An integrated encyclopedia of DNA elements in the human genome

12925Citations
N/AReaders
Get full text

TopHat2: Accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions

9862Citations
N/AReaders
Get full text

Cited by Powered by Scopus

Regulatory activities of transposable elements: From conflicts to benefits

865Citations
N/AReaders
Get full text

Transcription factor–DNA binding: beyond binding site motifs

239Citations
N/AReaders
Get full text

HLA-G: At the Interface of Maternal–Fetal Tolerance

228Citations
N/AReaders
Get full text

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Cite

CITATION STYLE

APA

Ferreira, L. M. R., Meissner, T. B., Mikkelsen, T. S., Mallard, W., O’Donnell, C. W., Tilburgs, T., … Strominger, J. L. (2016). A distant trophoblast-specific enhancer controls HLA-G expression at the maternal-fetal interface. Proceedings of the National Academy of Sciences of the United States of America, 113(19), 5364–5369. https://doi.org/10.1073/pnas.1602886113

Readers over time

‘16‘17‘18‘19‘20‘21‘22‘23‘24‘2508162432

Readers' Seniority

Tooltip

PhD / Post grad / Masters / Doc 57

60%

Researcher 30

32%

Professor / Associate Prof. 6

6%

Lecturer / Post doc 2

2%

Readers' Discipline

Tooltip

Biochemistry, Genetics and Molecular Bi... 45

48%

Agricultural and Biological Sciences 31

33%

Immunology and Microbiology 10

11%

Medicine and Dentistry 8

9%

Save time finding and organizing research with Mendeley

Sign up for free
0