气候变化领域集成服务门户(CCPortal): ELF3 activated by a superenhancer and an autoregulatory feedback loop is required for high-level HLA-C expression on extravillous trophoblasts

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DOI	10.1073/pnas.2025512118
	ELF3 activated by a superenhancer and an autoregulatory feedback loop is required for high-level HLA-C expression on extravillous trophoblasts
	Li Q.; Meissner T.B.; Wang F.; Du Z.; Ma S.; Kshirsagar S.; Tilburgs T.; Buenrostro J.D.; Uesugi M.; Strominger J.L.
发表日期	2021
ISSN	00278424
卷号	118 期号:9
英文摘要	HLA-C arose during evolution of pregnancy in the great apes 10 to 15 million years ago. It has a dual function on placental extravillous trophoblasts (EVTs) as it contributes to both tolerance and immunity at the maternal-fetal interface. The mode of its regulation is of considerable interest in connection with the biology of pregnancy and pregnancy abnormalities. First-trimester primary EVTs in which HLA-C is highly expressed, as well as JEG3, an EVT model cell line, were employed. Single-cell RNA-seq data and quantitative PCR identified high expression of the transcription factor ELF3 in those cells. Chromatin immunoprecipitation (ChIP)PCR confirmed that both ELF3 and MED1 bound to the proximal HLA-C promoter region. However, binding of RFX5 to this region was absent or severely reduced, and the adjacent HLA-B locus remained closed. Expression of HLA-C was inhibited by ELF3 small interfering RNAs (siRNAs) and by wrenchnolol treatment. Wrenchnolol is a cell-permeable synthetic organic molecule that mimics ELF3 and is relatively specific for binding to ELF3's coactivator, MED23, as our data also showed in JEG3. Moreover, the ELF3 gene is regulated by a superenhancer that spans more than 5 Mb, identified by assay for transposase-accessible chromatin using sequencing (ATAC-seq), as well as by its sensitivity to (+)-JQ1 (inhibitor of BRD4). ELF3 bound to its own promoter, thus creating an autoregulatory feedback loop that establishes expression of ELF3 and HLA-C in trophoblasts. Wrenchnolol blocked binding of MED23 to ELF3, thus disrupting the positive-feedback loop that drives ELF3 expression, with down-regulation of HLA-C expression as a consequence. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	(+)-JQ1; Autoregulatory feedback loop; ELF3; HLA-C; Superenhancer
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180503
作者单位	Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, United States; Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02115, United States; Department of Surgery, Harvard Medical School, Boston, MA 02115, United States; Department of Obstetrics and Gynecology, Zhongnan Hospital, Wuhan University, Hubei, 430072, China; Department of Molecular Diagnostics, Sun Yat-sen University, Cancer Center, Guangzhou, 510060, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Cancer Center, Guangzhou, 510060, China; Division of Immunobiology, Center for Inflammation and Tolerance, Cincinnati Children's Hospital, Cincinnati, OH 45229, United States; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH 45229, United States; World Premier International Research Center Initiative for Integrated Cell-Material Sciences, Kyoto University, Kyoto, 61...
推荐引用方式 GB/T 7714	Li Q.,Meissner T.B.,Wang F.,et al. ELF3 activated by a superenhancer and an autoregulatory feedback loop is required for high-level HLA-C expression on extravillous trophoblasts[J],2021,118(9).
APA	Li Q..,Meissner T.B..,Wang F..,Du Z..,Ma S..,...&Strominger J.L..(2021).ELF3 activated by a superenhancer and an autoregulatory feedback loop is required for high-level HLA-C expression on extravillous trophoblasts.Proceedings of the National Academy of Sciences of the United States of America,118(9).
MLA	Li Q.,et al."ELF3 activated by a superenhancer and an autoregulatory feedback loop is required for high-level HLA-C expression on extravillous trophoblasts".Proceedings of the National Academy of Sciences of the United States of America 118.9(2021).