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Effect of ELF3 and NLRP7 depletion on gene expression in JEG-3 cells

ABSTRACT: The distinct Class I MHC expression pattern in extravillous trophoblasts (EVT) endows them with immune-tolerant properties that enable successful pregnancy. Notwithstanding, it remains elusive how this process is elaborately regulated. Previously, we identified ELF3 as a transcription factor that governs high level HLA-C expression in EVT. In this study, we found that ELF3 also binds to the enhancer region of two NLR genes, NLRP2 and NLRP7, transactivating NLRP7 expression while suppressing expression of NLRP2. We confirmed that NLRP2 suppresses HLA-C expression while in this study we described a novel role for NLRP7 promoting HLA-C expression in trophoblasts. These two NLR genes, highly expressed in trophoblasts, are thus fine-tuned by ELF3 and enable proper expression of HLA-C in trophoblasts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241792 | GEO | 2023/09/05

REPOSITORIES: GEO

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ELF3 activated by a super-enhancer and an autoregulatory feedback loop is required for high level HLA-C expression on extravillous trophoblasts

Project description:HLA-C arose during evolution of pregnancy in the Great Apes 10-15 million years ago. It has a dual function on placental extravillous trophoblasts (EVT) 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 EVT in which HLA-C is highly expressed, as well as JEG3, an EVT model cell lines, were employed. Single cell RNA-seq data and quantitative PCR identified high expression of the transcription factor ELF3 in those cells. 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 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 super-enhancer that spans more than 5 Mb, identified by 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.

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2015-05-15 | E-MTAB-3217 | biostudies-arrayexpress

Oxysterols Modify NLRP2 in Epithelial Cells, Identifying a Mediator of Ozone-induced Inflammation.

Project description:Ozone (O3) is a prevalent air pollutant that causes lung inflammation following exposure. Previous studies demonstrate that O3 oxidizes lipids, such as cholesterol, in the airway to produce oxidized cholesterol products (oxysterols), such as secosterol-A (secoA), which form covalent linkages preferentially with lysine residues and consequently modify protein function. The breadth of proteins modified by this oxysterol as well as the biological consequences in the lung are unknown. Using an alkynyl-tagged form of secosterol-A and shotgun proteomics, we identified NLR Family Pyrin Domain Containing 2 (NLRP2) to be adducted at lysine (K1019) in the terminal leucine-rich-repeat, a known regulatory region for NLR proteins. We characterized NLRP2 expression in airway epithelial cells and used CRISPR-Cas9 knockout and shRNA knockdown of NLRP2 for analysis of inflammasome complex activity and pro-inflammatory mediator production following O3 exposure. We observed an increase in caspase-1 activity in response to O3, which was not altered by knocked down NLRP2 expression. O3-induced pro-inflammatory gene expression for CXCL1, CXCL2, and IL8 was further enhanced in NLRP2 knockout cells. Together, our findings uncover NLRP2 as a highly abundant, key component of pro-inflammatory signaling pathways in airway epithelial cells and formation of oxysterol-NLRP2 adduct as a novel mediator of O3-induced inflammation.

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Project description:Invasive extravillous trophoblasts (EVTs) of the human placenta are critically involved in successful pregnancy outcome since they remodel the uterine spiral arteries to increase blood flow and oxygen delivery to the placenta and the developing fetus. To gain more insights into their biological role different primary cell culture models are commonly utilised. However, access to early placental tissue may be limited and primary trophoblasts rapidly cease proliferation in vitro impairing genetic manipulation. Hence, trophoblastic cell lines have been widely used as surrogates to study EVT function. Although the cell lines share some molecular marker expression with their primary counterpart, it is unknown to what extent they recapture the invasive phenotype of EVT. Therefore, we here report the first thorough GeneChip analyses of SGHPL-5, HTR-8/SVneo, BeWo, JEG-3 and the novel ACH-3P trophoblast cells in comparison to previously analysed primary villous cytrophoblasts and extravillous trophoblasts. To identify EVT-specific gene expression signatures in trophoblast cell lines, we calcuted differentially expressed genes between pre-defined groups based on the distinct origins of the five trophoblast cell lines under investigation. Comparison 1 comprised EVT, HTR-8/Svneo and SGHPL-5 vs choriocarcinoma cells (ACH-3P, BeWo, JEG-3). Comparison 2 comprised EVT, ACH-3P, BeWo, JEG-3 vs extravillous trophoblast cell lines (HTR-8/SVneo, SGHPL-5).

2010-09-23 | E-GEOD-20510 | biostudies-arrayexpress

An improved protocol for targeted differentiation of human iPSCs into HLA-G expressing trophoblasts cells enabling modelling of placenta-related disorders.

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2023-09-14 | GSE234949 | GEO

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Defining key transcriptional regulators of extravillous trophoblast differentiation [RNA-seq]

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