Maternal ELL3 loss-of-function leads to oocyte aneuploidy and early miscarriage
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE268181 | GEO | 2024/10/30
REPOSITORIES: GEO
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Project description:Maternal ELL3 loss-of-function leads to oocyte aneuploidy and early miscarriage
| PRJNA1115055 | ENA
Project description:Ell3 is a RNA polymerase II transcription elongation factor that is enriched in testis. The C-terminal domain of Ell3 shows strong similarities to that of Ell (eleven-nineteen lysine-rich leukemia gene), which acts as a negative regulator of p53 and regulates cell proliferation and survival. Recent studies in our laboratory showed that Ell3 induces the differentiation of mouse embryonic stem cells by protecting differentiating cells from apoptosis via the promotion of p53 degradation. In this study, we evaluated the function of Ell3 in breast cancer cell lines. MCF7 cell lines overexpressing Ell3 were used to examine cell proliferation and cancer stem cell properties. Ectopic expression of Ell3 in breast cancer cell lines induces proliferation and 5-FU resistance. In addition, Ell3 expression increases the cancer stem cell population, which is characterized by CD44 (+) or ALDH1 (+) cells. Mammosphere-forming potential and migration ability were also increased upon Ell3 expression in breast cancer cell lines. Through biochemical and molecular biological analyses, we showed that Ell3 regulates proliferation, cancer stem cell properties and drug resistance in breast cancer cell lines partly through the MEK-extracellular signal-regulated kinase signaling pathway. Murine xenograft experiments showed that Ell3 expression promotes tumorigenesis in vivo. The transcription elongation factor Ell3 induces chemosensitization of MCF7 cells to the chemotherapeutic agent cis-diamminedichloroplatinum (II) (CDDP) by stabilizing p53. Interestingly, Ell3 induced p53 stabilization in response to CDDP by promoting binding of p53 to NADH quinoneoxidoreductase 1 (NQO1), which is linked to an ubiquitin-independent degradation pathway, as well as by suppressing a MDM2 mediated ubiquitin-dependent degradation pathway. Furthermore, Ell3 enhanced interleukin-20 (IL-20) expression leading to the activation of the ERK1/2 signaling pathway. By analyzing the suppressive effects of IL-20 and ERK signaling in the Ell3 expressing MCF7 cells, we confirmed that the IL-20 mediated ERK1/2 signaling pathway is the main cause of p53 stabilization after CDDP exposure in MCF7 cells. Ell3-overexpressing breast cancer cell lines were established using the chromosomal integration of an Ell3 expression plasmid, which was constructed by cloning PCR-amplified Ell3 cDNA into pcDNA3.1 vectors (Invitrogen, Carlsbad, CA; https://www.lifetechnologies.com). Three independent Ell3 overexpressing cell lines were generated. The gene expression profiles of wild type MCF7 and Ell3 overexpressing cell line were compared using Affymetrix PrimeView arrays.
2015-11-25 | E-GEOD-63612 | biostudies-arrayexpress
Project description:Ell3 is a RNA polymerase II transcription elongation factor that is enriched in testis. The C-terminal domain of Ell3 shows strong similarities to that of Ell (eleven-nineteen lysine-rich leukemia gene), which acts as a negative regulator of p53 and regulates cell proliferation and survival. Recent studies in our laboratory showed that Ell3 induces the differentiation of mouse embryonic stem cells by protecting differentiating cells from apoptosis via the promotion of p53 degradation. In this study, we evaluated the function of Ell3 in breast cancer cell lines. MCF7 cell lines overexpressing Ell3 were used to examine cell proliferation and cancer stem cell properties. Ectopic expression of Ell3 in breast cancer cell lines induces proliferation and 5-FU resistance. In addition, Ell3 expression increases the cancer stem cell population, which is characterized by CD44 (+) or ALDH1 (+) cells. Mammosphere-forming potential and migration ability were also increased upon Ell3 expression in breast cancer cell lines. Through biochemical and molecular biological analyses, we showed that Ell3 regulates proliferation, cancer stem cell properties and drug resistance in breast cancer cell lines partly through the MEK-extracellular signal-regulated kinase signaling pathway. Murine xenograft experiments showed that Ell3 expression promotes tumorigenesis in vivo. The transcription elongation factor Ell3 induces chemosensitization of MCF7 cells to the chemotherapeutic agent cis-diamminedichloroplatinum (II) (CDDP) by stabilizing p53. Interestingly, Ell3 induced p53 stabilization in response to CDDP by promoting binding of p53 to NADH quinoneoxidoreductase 1 (NQO1), which is linked to an ubiquitin-independent degradation pathway, as well as by suppressing a MDM2 mediated ubiquitin-dependent degradation pathway. Furthermore, Ell3 enhanced interleukin-20 (IL-20) expression leading to the activation of the ERK1/2 signaling pathway. By analyzing the suppressive effects of IL-20 and ERK signaling in the Ell3 expressing MCF7 cells, we confirmed that the IL-20 mediated ERK1/2 signaling pathway is the main cause of p53 stabilization after CDDP exposure in MCF7 cells.
2015-11-25 | GSE63612 | GEO
Project description:Enhancers play a central role in precisely regulating the spatiotemporal expression of developmentally regulated genes. The molecular mechanisms and factors required for controlling the inactive or poised enhancers and their function in future gene activation remain elusive. Here, we have identified that Ell3, a member of the Ell (Eleven-nineteen Lysine-rich Leukemia gene) family of RNA Pol II elongation factors, predominately occupies active and inactive enhancers of many developmentally regulated genes in mouse embryonic stem cells. Ell3 localizes to active enhancers of key stem cell renewal genes, but is not required for maintaining the undifferentiated state. Instead, Ell3 binding to inactive or poised enhancers is essential for marking them for stem cell specification through regulating the activation of key lineage-specific genes throughout differentiation. Ell3M-bM-^@M-^Ys association with enhancers is required for setting up proper Pol II occupancy at the proximal promoter regions of neighboring genes. This functional interaction between Ell3 and proximal promoter Pol II is dependent on cohesin. The depletion of cohesin subunits removes Ell3 from the enhancers and results in reduction in the levels of promoter proximally paused Pol II. Our study demonstrates that Ell3 is required for stem cell fate specification through regulating Pol II pausing on key developmental genes in the undifferentiated state and for their proper expression during differentiation. ChIP-seq of Ell3 in mES cells. ChIP-seq of Pol II in mES cells after Ell3 shRNA and non-targeting shRNA. RNA-seq of mES cells after Ell3 shRNA and non-targeting shRNA. RNA-seq of mouse embryoid bodies at day five after non-targeting shRNA.
2012-12-30 | E-GEOD-38148 | biostudies-arrayexpress
Project description:siblings of patients with idiopathic recurrent miscarriage have a higher risk of miscarriage. <br>We hypothesized that this in part was conferred by shared genetic factors.<br>We took blood samples from patients with three or more miscarriages and from siblings with two or more miscarriages in order to perform affected sib-pair analysis.
2010-12-01 | E-MEXP-2942 | biostudies-arrayexpress
Project description:Tumors that overexpress the MYC oncogene frequently demonstrate aneuploidy, numerical chromosome alterations associated with highly aggressive cancers, rapid tumor evolution, and poor patient outcome. Here, we identify that MYC overexpression induces defects in microtubule nucleation and mitotic spindle assembly, promoting chromosome segregation defects, micronuclei and chromosomal instability (CIN). High TPX2 expression is permissive for mitotic spindle assembly and chromosome segregation in cells with MYC overexpression; whereas TPX2 depletion blocks mitotic progression, induces cell death and prevents tumor growth. Attenuating MYC expression reverses mitotic defects, even in established tumor cell lines, implicating an ongoing role for high MYC in the persistence of CIN in tumors. Our studies implicate the MYC oncogene as a regulator of spindle assembly and identify a new MYC-TPX2 synthetic-lethal interaction that could represent a future therapeutic strategy in MYC-overexpressing cancers. Moreover, our studies suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution.
2020-03-30 | GSE130921 | GEO
Project description:Tumors that overexpress the MYC oncogene frequently demonstrate aneuploidy, numerical chromosome alterations associated with highly aggressive cancers, rapid tumor evolution, and poor patient outcome. Here, we identify that MYC overexpression induces defects in microtubule nucleation and mitotic spindle assembly, promoting chromosome segregation defects, micronuclei and chromosomal instability (CIN). High TPX2 expression is permissive for mitotic spindle assembly and chromosome segregation in cells with MYC overexpression; whereas TPX2 depletion blocks mitotic progression, induces cell death and prevents tumor growth. Attenuating MYC expression reverses mitotic defects, even in established tumor cell lines, implicating an ongoing role for high MYC in the persistence of CIN in tumors. Our studies implicate the MYC oncogene as a regulator of spindle assembly and identify a new MYC-TPX2 synthetic-lethal interaction that could represent a future therapeutic strategy in MYC-overexpressing cancers. Moreover, our studies suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution.
2020-03-30 | GSE130920 | GEO
Project description:Enhancers play a central role in precisely regulating the spatiotemporal expression of developmentally regulated genes. The molecular mechanisms and factors required for controlling the inactive or poised enhancers and their function in future gene activation remain elusive. Here, we have identified that Ell3, a member of the Ell (Eleven-nineteen Lysine-rich Leukemia gene) family of RNA Pol II elongation factors, predominately occupies active and inactive enhancers of many developmentally regulated genes in mouse embryonic stem cells. Ell3 localizes to active enhancers of key stem cell renewal genes, but is not required for maintaining the undifferentiated state. Instead, Ell3 binding to inactive or poised enhancers is essential for marking them for stem cell specification through regulating the activation of key lineage-specific genes throughout differentiation. Ell3’s association with enhancers is required for setting up proper Pol II occupancy at the proximal promoter regions of neighboring genes. This functional interaction between Ell3 and proximal promoter Pol II is dependent on cohesin. The depletion of cohesin subunits removes Ell3 from the enhancers and results in reduction in the levels of promoter proximally paused Pol II. Our study demonstrates that Ell3 is required for stem cell fate specification through regulating Pol II pausing on key developmental genes in the undifferentiated state and for their proper expression during differentiation.
2012-12-30 | GSE38148 | GEO
Project description:We identified gene expression signatures predicting responsiveness to a Kinesin-5 (kinesin spindle protein, KIF11) inhibitor (Kinesin-5i) in cultured colon tumor cell lines. Genes predicting resistance to Kinesin-5i were enriched for those from chromosome 20q, a region of frequent amplification in a number of tumor types. siRNAs targeting genes in this chromosomal region identified AURKA, TPX2 and MYBL2 as genes whose disruption enhances response to Kinesin-5i. Taken together, our results show functional interaction between these genes, and suggest that overexpression of AURKA, TPX2 and MYBL2 is functionally involved in resistance to Kinesin-5i. Furthermore, our results suggest that patients whose tumors overexpress AURKA due to amplifications of 20q will be more likely to resist treatment with Kinesin-5 inhibitor, and that inactivation of AURKA may sensitize these patients to treatment. Keywords: Cell line comparison
2008-01-01 | GSE7969 | GEO
Project description:Chromosome aneuploidy increases in oocytes with maternal age, and is considered the leading cause for the increased incidence of infertility, miscarriage, and birth defects. Using mRNA-Sequencing of oocytes from 12 month old mouse versus 3 month young mouse, we identified a spindle assembly checkpoint gene, BubR1, whose expression was significantly decreased. We employed a mRNA microinjection based approach to increase BubR1 expression in aging oocytes. We find that increased expression of BubR1 protects against aneuploidy and chromosome misalignment in aging oocytes. After in vitro fertilization, the embryos derived from BubR1 increased expression aging oocytes exhibited chromosome stability as robust as those of the young ones. Furthermore, following embryo transfer, these embryos showed greatly improved developmental competency, with comparable levels of full-term development to those of the young ones. These results indicate that the decline in oocyte quality may be reversible and could lead to treatments that prolong female fertility. Examination of the effect of maternal aging on the mRNA expression in the mature oocytes of the female mice. Naturally ovulated mature oocytes (MII stage) were collected from 6 young (3 month) and 6 aging (12 month) female mice (3 oocytes per mice, 18 oocytes for each group).
2014-05-10 | E-GEOD-57482 | biostudies-arrayexpress