Transcriptional Control of Maternal-Fetal Immune Tolerance

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Transcriptional Control of Maternal-Fetal Immune Tolerance

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Title: Transcriptional Control of Maternal-Fetal Immune Tolerance
Author: Ferreira, Leonardo ORCID  0000-0003-2491-9866
Citation: Ferreira, Leonardo. 2016. Transcriptional Control of Maternal-Fetal Immune Tolerance. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
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Abstract: Human leukocyte antigens (HLA) are important determinants of self-nonself immune recognition. HLA-G, uniquely expressed in the placenta, is believed to be key to fetus-induced immune tolerance during pregnancy. The tissue-specific expression of HLA-G, however, remains poorly understood. Using a Massively Parallel Reporter Assay (MPRA), we discovered a 121 bp sequence 12 kb upstream of HLA-G with enhancer activity, Enhancer L. Strikingly, deletion of Enhancer L using a CRISPR/Cas9 dual guide approach resulted in complete ablation of HLA-G expression in a trophoblast cell line. This finding was confirmed in primary extravillous trophoblasts isolated from human placenta. RNA-seq analysis demonstrated that Enhancer L regulates HLA-G expression specifically. Moreover, DNase-seq and Chromatin Conformation Capture (3C) defined Enhancer L as a cell type-specific enhancer that loops into the HLA-G promoter. GATA2, GATA3, and CEBPB, factors essential for placentation, associate with Enhancer L and regulate HLA-G expression levels. These results establish long-range chromatin looping as a novel mechanism controlling trophoblast-specific HLA-G expression at the maternal-fetal interface.
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