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Derepression of a single microRNA target causes female infertility in mice [RNA-Seq]

ABSTRACT: The miR-200a and miR-200b families control mouse ovulation and are essential for female fertility. The ZEB1 transcription factor is a conserved target of both families and has been implicated as a key player in female fertility at multiple levels. Using gene-edited mice that express a miR-200a/b-resistant form of Zeb1, we found that derepression of Zeb1 in the female pituitary caused decreased production of luteinizing hormone and anovulatory infertility. These phenotypes were accompanied by widespread changes in pituitary gene expression characterized by decreased levels of ZEB1 targets, which include the miR-200a/b miRNAs, as expected from the miR-200a/b–ZEB1 double-negative feedback loop. Also observed were increased levels of mesenchymal genes, neuronal genes, and miR-200a/b targets. These results show that a double-negative feedback loop centered on the miRNA regulation of a single transcription factor can significantly influence the expression of thousands of genes and have dramatic phenotypic consequences.

ORGANISM(S): Mus musculus

PROVIDER: GSE279446 | GEO | 2025/12/01

REPOSITORIES: GEO

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Derepression of a single microRNA target causes female infertility in mice [smallRNA-Seq]

Project description:The miR-200a and miR-200b families control mouse ovulation and are essential for female fertility. The ZEB1 transcription factor is a conserved target of both families and has been implicated as a key player in female fertility at multiple levels. Using gene-edited mice that express a miR-200a/b-resistant form of Zeb1, we found that derepression of Zeb1 in the female pituitary caused decreased production of luteinizing hormone and anovulatory infertility. These phenotypes were accompanied by widespread changes in pituitary gene expression characterized by decreased levels of ZEB1 targets, which include the miR-200a/b miRNAs, as expected from the miR-200a/b–ZEB1 double-negative feedback loop. Also observed were increased levels of mesenchymal genes, neuronal genes, and miR-200a/b targets. These results show that a double-negative feedback loop centered on the miRNA regulation of a single transcription factor can significantly influence the expression of thousands of genes and have dramatic phenotypic consequences.

2025-12-01 | GSE279447 | GEO

Down-regulation of miR-200a-3p, targeting C-terminal binding protein-2 (CtBP2), is involved in hypoproduction of IL-2 in SLE-derived T cells

Project description:Systemic lupus erythematosus (SLE) damages multiple organs by producing various autoantibodies. Insufficient interleukin-2 (IL-2) production causes decreased regulatory T cells and permits expansion of autoreactive T cells in the development of SLE. We here show that decreased miR-200a-3p causes IL-2 hypoproduction through directly recruiting ZEB1 or ZEB2 and CtBP2 (ZEB1/ZEB2-CtBP2) complex in SLE T cells. First, we performed RNA sequencing with Illumina Hiseq to obtain the candidate miRNAs and mRNAs involved in the pathogenesis of SLE. We found that miR-200a-3p was significantly downregulated, while its putative targets, ZEB2 and CtBP2 were upregulated in CD4+ T cells in MRL/lpr lupus model mice compared with those of C57BL/6J control mice. ZEB1 and ZEB2 compose ZEB family and suppress various genes including IL-2 by recruiting CtBP2. IL-2 plays a critical role in immune tolerance and IL-2 defect has been recognized in SLE pathogenesis. Therefore, we hypothesized that decreased miR-200a-3p cause IL-2 defect through ZEB1/ZEB2-CtBP2 complex in SLE CD4+T cells. Overexpression of miR-200a-3p induced IL-2 production though downregulating ZEB1, ZEB2 and CtBP2 in EL4 cell lines. We further revealed that miR-200a-3p promote IL-2 expression by reducing the bindings of suppressive ZEB1/ZEB2-CtBP2 complex on NRE-A of IL-2 promoter in SLE murine T cells. Interestingly, ZEB1/ZEB2-CtBP2 complex on NRE-A (a negative regulatory element) were significantly upregulated after phorbol-12-myristate-13-acetate and ionomycin (PMA/Iono) stimulation in lupus T cells. Our findings provide a new insight for the epigenetic regulation of IL-2 defect in SLE.

2016-09-23 | GSE87219 | GEO

microRNA profiles of meningiomas

Project description:Meningiomas, one of the most common human brain tumors, are derived from arachnoidal cells associated with brain meninges, usually benign and frequently associated with neurofibromatosis type 2. Here we define a human meningioma-typical miRNA profile and characterize effects of one down-regulated miRNA, miR-200a, on tumor growth. Elevated levels of miR-200a inhibited meningioma cell growth in culture and in a tumor model in vivo. Up-regulation of miR-200a decreased expression of transcription factors, ZEB1 and SIP1, with consequently increased expression of E-cadherin, an adhesion protein associated with cell differentiation. Down-regulation of miR-200a in meningiomas and arachnoidal cells resulted in increased expression of Î² -catenin and cyclin D1 involved in cell proliferation. miR-200a was found to directly target Î² -catenin mRNA, thereby inhibiting its translation and blocking Î² -catenin-Wnt signaling, frequently involved in cancer. A direct correlation was found between down-regulation of miR-200a and up-regulation of Î²-catenin in human meningioma samples. Thus, miR-200a appears to act as a multi-functional tumor suppressor miRNA in meningiomas through effects on the E-cadherin and Î² -catenin-Wnt signaling pathways. This reveals a previously unrecognized signaling cascade involved in meningioma tumor development and highlights a novel molecular interaction between miR-200a and Wnt signaling, thereby providing insights into novel therapies for meningiomas. 14 meningioma tumor samples were compared to 3 arachnoidal tissue control samples. Two technical replicates were performed for each sample. Normalization and processing included combining the data from technical replicates. The below table contains quantile-normalized data.

2010-06-24 | E-GEOD-17792 | biostudies-arrayexpress

microRNA profiles of meningiomas

Project description:Meningiomas, one of the most common human brain tumors, are derived from arachnoidal cells associated with brain meninges, usually benign and frequently associated with neurofibromatosis type 2. Here we define a human meningioma-typical miRNA profile and characterize effects of one down-regulated miRNA, miR-200a, on tumor growth. Elevated levels of miR-200a inhibited meningioma cell growth in culture and in a tumor model in vivo. Up-regulation of miR-200a decreased expression of transcription factors, ZEB1 and SIP1, with consequently increased expression of E-cadherin, an adhesion protein associated with cell differentiation. Down-regulation of miR-200a in meningiomas and arachnoidal cells resulted in increased expression of β -catenin and cyclin D1 involved in cell proliferation. miR-200a was found to directly target β -catenin mRNA, thereby inhibiting its translation and blocking β -catenin-Wnt signaling, frequently involved in cancer. A direct correlation was found between down-regulation of miR-200a and up-regulation of β-catenin in human meningioma samples. Thus, miR-200a appears to act as a multi-functional tumor suppressor miRNA in meningiomas through effects on the E-cadherin and β -catenin-Wnt signaling pathways. This reveals a previously unrecognized signaling cascade involved in meningioma tumor development and highlights a novel molecular interaction between miR-200a and Wnt signaling, thereby providing insights into novel therapies for meningiomas.

2009-08-25 | GSE17792 | GEO

TGFb treated EpRAS cells undergoing hysteretic vs non-hysteretic EMT gene expression analysis.

Project description:EpRAS cells undergo EMT transition through hysteresis showing bistability of the system. The hysteresis transition is controlled by the negative feedback loop between miR-200s and Zeb1. Disruption of the feedback loop through the deletion of Z-box2 in the miR-200s cluster-2 promoter region changes the transition to unimodal without hysteresis. To determine the consequence of cells undergoing through hysteresis or unimodal transitions of EMT, herein we determined the transcriptomic profiles of EpRAS wild type and EpRAS-delZbox2 mutant cells, (designated as EpRAS-C2-2). To induce EMT, the cells were treated with 100pM TGFbeta for 3 days. Mock PBS treatment is used as control.

2018-11-08 | GSE106533 | GEO

miR-29a/b1 regulates the pituitary gland luteinizing hormone secretion and affects mouse ovulation

Project description:miR-29a/b1 was reported to be involved in the regulation of reproductive function in female mice, but the underlying molecular mechanisms were not clear. In this study, female mice lacking miR-29a/b1 showed a delay in vaginal opening, irregular estrus cycles, ovulation disorder and infertility. However, the development of egg was normal in mutant mice and the ovulation disorder could be rescued by the superovulation treatment. The plasma level of luteinizing hormone (LH) was significantly lower in the mutant mice. Using iTRAQ coupled with LC-MS/MS, we found that the deficiency of miR-29a/b1 in mice resulted in an abnormal expression of a number of proteins involved in vesicular transport and secretion in the pituitary gland. The miR-29a/b1 targeting gene Dnmt3a and Hdac4 were up-regulated in the pituitary of miR-29a/b1 knockout mice suggesting that these two epigenetic writers may be the upstream causes for these phenotype changes due to miR-29a/b1 deficiency. These findings demonstrated that miR-29a/b1 is indispensable for the function of the reproductive axis through regulating LH secretion in the pituitary gland.

2021-09-09 | PXD017106 | Pride

MiR-200a Regulates CDK4/6 Inhibitor Effect by Targeting CDK6 in Metastatic Melanoma

Project description:Three metastatic melanoma cell lines (BD-0548-ME, DP-0574-ME and WP-0614-ME) were transfected with miR precursors: hsa-miR negative control (NC) or hsa-miR-200a-3p precursors (miR-200a). The objective of this experiment was to determine miR-200a targets in metastatic melanoma cell lines. We selected low -miR-200a expression cell lines and then we overexpressed miR-200a or NC. Finally, we compared the metastatic melanoma cell lines with miR-200a overexpression (miR-200a) to the same cell line transfected with the negative control miR (NC).

2018-06-20 | GSE83512 | GEO

The miR-200 Family and their Targets in Regulation of Type II Cell Differentiation in Human Fetal Lung

Project description:Type II cell differentiation and expression of the major surfactant protein, SP-A, in midgestation human fetal lung (HFL) are markedly induced by cAMP and inhibited by TGF-β. cAMP induction of SP-A promoter activity is mediated by increased phosphorylation and in vivo binding of TTF-1/Nkx2.1, a critical transcription factor in lung development. To further define mechanisms for developmental induction of surfactant synthesis in HFL, herein, we investigated the potential role of microRNAs (miRNAs, miRs). To identify and characterize differentially regulated miRNAs in mid-gestation HFL explants during type II pneumocyte differentiation in culture, we performed miRNA microarray analysis of RNA isolated from epithelial cells from midgestation HFL explants before and after culture ± Bt2cAMP. Interestingly, the miR-200 family was significantly upregulated during type II cell differentiation; miR-200 family induction was inversely correlated with expression of its known targets, transcription factors ZEB1 and ZEB2, and TGF-b2. miR-200 antagonists inhibited TTF-1 and SP-A expression and upregulated TGF-β2 and ZEB1 expression in type II cells. Overexpression of ZEB1 in cultured type II cells decreased DNA binding of endogenous TTF-1, blocked cAMP stimulation of SP-A and inhibited miR-200 expression,whereas, cAMP markedly inhibited ZEB1/2 and TGF-β. Importantly, overexpression of ZEB1 or miR-200 antagonists in HFL type II cells markedly suppressed accumulation of lamellar bodies, organelles that store surfactant. Our findings suggest that the miR-200 family and ZEB1, which exist in a double-negative feedback loop regulated by TGF-β, serve important regulatory roles in the developmental regulation of type II cell differentiation and SP-A expression in HFL.

2015-10-01 | GSE61183 | GEO

lncRNA and mRNA expression signatures in OVCAR3 cells: control vs. miR-200a transfected

Project description:To further development of the effects of miR-200a in ovarian cancer OVCAR3 cells，we have employed lncRNA and mRNA microarray as a discovery platform to identify lncRNA and mRNA expression in miR-200a overexpressing ovarian cancer cells. OVCAR3 cells were transfected with lentiviral vector with eGFP, encoding miR-200a and negative control vector (LV- miR-200a and LV-CON,) by using polybrene. The dysregulation of miR-200a was confirmed by using RT-PCR. RNA was extracted and detected by a lncRNA and mRNA microarray in LV-miR-200a and LV-CON OVCAR3 cells. The different expression of lncRNA and mRNA in LV-miR-200a and LV-CON OVCAR3 cells was analyzed to explore the mechanism that miR-200a affect ovarain cancer cells.

2018-11-04 | GSE122123 | GEO

A functional link between miR-200a and ELK3 regulates the metastatic nature of breast cancer

Project description:The ectopic expression of miR-200a impaired the migration and invasion of TNBC cells by reducing the expression level of the ELK3 mRNA. An analysis of differentially expressed genes showed that the control group - and miR-200a plus ELK3 group had similar genetic signatures that differed from that of the miR-200a alone group.

2020-04-14 | GSE148562 | GEO

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