Mediator Med23 regulates adult hippocampal neurogenesis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE152113 | GEO | 2020/06/10
REPOSITORIES: GEO
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Project description:Mediator Med23 regulates adult hippocampal neurogenesis
| PRJNA638362 | ENA
Project description:Mammalian Mediator (Med) is a key regulator of gene expression by linking transcription factors to RNA polymerase II (Pol II) transcription machineries. The Mediator subunit 23 (Med23) is a member of the conserved Med protein complex and plays essential roles in diverse biological processes including adipogenesis, carcinogenesis, osteoblast differentiation, and T-cell activation. However, its potential functions in the nervous system remain unknown. We report here that Med23 is required for adult hippocampal neurogenesis in mouse. Deletion of Med23 in adult hippocampal neural stem cells (NSCs) was achieved in Nestin-CreER:Med23flox/flox mice by oral administration of tamoxifen. We found an increased number of proliferating NSCs shown by pulse BrdU-labeling and immunostaining of MCM2 and Ki67, which is possibly due to a reduction in cell cycle length, with unchanged GFAP+/Sox2+ NSCs and Tbr2+ progenitors. On the other hand, neuroblasts and immature neurons indicated by NeuroD and DCX were decreased in number in the dentate gyrus (DG) of Med23-deficient mice. In addition, these mice also displayed defective dendritic morphogenesis, as well as a deficiency in spatial and contextual fear memory. Gene ontology (GO) analysis of hippocampal NSCs revealed an enrichment in genes involved in cell proliferation, Pol II-associated transcription, Notch signaling pathway and apoptosis. These results demonstrate that Med23 plays roles in regulating adult brain neurogenesis and functions.
| S-EPMC7403405 | biostudies-literature
Project description:K-RAS activating mutations occur frequently in non-small cell lung cancer (NSCLC), leading to aberrant activation of Ras-MAPK signaling pathway that contributes to the malignant phenotype. However, the development of Ras-targeted therapeutics remains challenging. Here, we show that MED23, a component of the multisubunit Mediator complex that is known to integrate signaling and gene activities, is selectively important for Ras-active lung cancer. By screening a large panel of human lung cancer cell lines with or without a Ras mutation, we found that Med23 RNAi specifically inhibits the proliferation and tumorigenicity of lung cancer cells with hyperactive Ras activity. Med23-deficiency in fibroblasts selectively inhibited the oncogenic transformation induced by Ras but not by c-Myc. Transcription factor ELK1, which is phosphorylated by MAPK for relaying the Ras signaling to MED23, was also required for the Ras-driven oncogenesis. Transcriptiome analysis revealed that MED23 and ELK1 co-regulate a common set of target genes enriched in regulating cell cycle and proliferation to support the Ras-dependency. Furthermore, correlated with the strength of Ras signaling as indicated by the ELK1 phosphorylation level, MED23 was up-regulated by Ras-transformation, and was found to be overexpressed in both Ras-mutated lung cancer cell lines and primary tumor samples. Remarkably, lower Med23 expression predicts better survival in Ras-active lung cancer patients and xenograft mice. Collectively, our findings demonstrate a critical role for MED23 in enabling the 'Ras-addiction' of lung carcinogenesis, thus providing a vulnerable target for the treatment of Ras-active lung cancer. To gain a genome-wide understanding of how MED23 and ELK1 control gene expression in Ras-active lung cancer cells, we performed gene profiling experiments to analyze the transcriptomes from control, si-Med23, or si-Elk1 A549 cells. The si-Ctrl, si-Med23 and si-Elk1 A549 cells were cultured in the normal condition. Then the cells were harvested for RNA extraction and hybridization on Affymetrix microarrays. The analysis contain 9 samples. si-Ctrl cells have three replicates (si-Ctrl#1, si-Ctrl#2 and si-Ctrl#3), and the si-Med23 or si-Elk1 group contains three different cell lines that harbor three different RNAi oligos against Med23 or Elk1 (si-Med23A, B, C and si-Elk1A, B, C).
2013-08-31 | E-GEOD-40517 | biostudies-arrayexpress
Project description:Mediator complex is an integrative hub for transcriptional regulation. Here we show that Mediator regulates alternative mRNA processing via its Med23 subunit. Combining tandem affinity purification and mass spectrometry, we identified a number of mRNA processing factors that bind to a soluble recombinant Mediator subunit MED23 but not to several other Mediator components. One of these factors, hnRNP L, specifically interacts with MED23 in vitro and in vivo. Consistently, Mediator partially colocalizes with hnRNP L and the splicing machinery in the cell. Functionally Med23 regulates a subset of hnRNP L-targeted alternative splicing (AS) and alternative cleavage and polyadenylation (APA) events as shown by minigene reporters and exon array analysis. ChIP-seq analysis revealed that Med23 can regulate hnRNP L occupancy at their co-regulated genes. Taken together, these results demonstrate a crosstalk between Mediator and the splicing machinery, suggesting a novel mechanism for coupling mRNA processing to transcription. We performed an exon array experiment using HeLa cells expressing Med23, hnRNP L or control siRNAs which were established by a virus-mediated siRNA technology. Each sample was done in three biological replicates. Total RNA of these cell lines was processed and hybridized to the Affymetrix human exon array.
2012-02-24 | E-GEOD-33771 | biostudies-arrayexpress
Project description:Mediator complex is an integrative hub for transcriptional regulation. Here we show that Mediator regulates alternative mRNA processing via its Med23 subunit. Combining tandem affinity purification and mass spectrometry, we identified a number of mRNA processing factors that bind to a soluble recombinant Mediator subunit MED23 but not to several other Mediator components. One of these factors, hnRNP L, specifically interacts with MED23 in vitro and in vivo. Consistently, Mediator partially colocalizes with hnRNP L and the splicing machinery in the cell. Functionally Med23 regulates a subset of hnRNP L-targeted alternative splicing (AS) and alternative cleavage and polyadenylation (APA) events as shown by minigene reporters and exon array analysis. ChIP-seq analysis revealed that Med23 can regulate hnRNP L occupancy at their co-regulated genes. Taken together, these results demonstrate a crosstalk between Mediator and the splicing machinery, suggesting a novel mechanism for coupling mRNA processing to transcription. Examination of hnRNP L and H3K36me3 enrichment in sictrl and si23 Hela cells
2012-02-24 | E-GEOD-33887 | biostudies-arrayexpress
Project description:Liver fibrosis, often associated with cirrhosis and hepatocellular carcinomas, is characterized by hepatic damage, an inflammatory response, and hepatic stellate cell (HSC) activation, although the underlying mechanisms are largely unknown.Here,we show that the MED23 subunit of the transcriptional Mediator complex participates in the development of experimental liver fibrosis. Compared with their control littermates, mice with hepatic Med23 deletion exhibited aggravated CCl4-induced liver fibrosis, with enhanced chemokine production and inflammatory infiltration as well as increased hepatocyte regeneration. Mechanistically, the orphan nuclear receptor RORα activates the expression of the liver fibrosis-related chemokines CCL5 and CXCL10, which is suppressed by the Mediator subunit MED23. We further found that the inhibition of Ccl5 and Cxcl10 expression by MED23 likely occurs due to G9a-mediated H3K9 dimethylation of the target promoters. Collectively, these findings reveal hepatic MED23 as a key modulator of chemokine production and inflammatory responses and define the MED23-CCL5/CXCL10 axis as a potential target for clinical intervention in liver fibrosis.
2020-06-06 | GSE137457 | GEO
Project description:K-RAS activating mutations occur frequently in non-small cell lung cancer (NSCLC), leading to aberrant activation of Ras-MAPK signaling pathway that contributes to the malignant phenotype. However, the development of Ras-targeted therapeutics remains challenging. Here, we show that MED23, a component of the multisubunit Mediator complex that is known to integrate signaling and gene activities, is selectively important for Ras-active lung cancer. By screening a large panel of human lung cancer cell lines with or without a Ras mutation, we found that Med23 RNAi specifically inhibits the proliferation and tumorigenicity of lung cancer cells with hyperactive Ras activity. Med23-deficiency in fibroblasts selectively inhibited the oncogenic transformation induced by Ras but not by c-Myc. Transcription factor ELK1, which is phosphorylated by MAPK for relaying the Ras signaling to MED23, was also required for the Ras-driven oncogenesis. Transcriptiome analysis revealed that MED23 and ELK1 co-regulate a common set of target genes enriched in regulating cell cycle and proliferation to support the Ras-dependency. Furthermore, correlated with the strength of Ras signaling as indicated by the ELK1 phosphorylation level, MED23 was up-regulated by Ras-transformation, and was found to be overexpressed in both Ras-mutated lung cancer cell lines and primary tumor samples. Remarkably, lower Med23 expression predicts better survival in Ras-active lung cancer patients and xenograft mice. Collectively, our findings demonstrate a critical role for MED23 in enabling the “Ras-addiction” of lung carcinogenesis, thus providing a vulnerable target for the treatment of Ras-active lung cancer. To gain a genome-wide understanding of how MED23 and ELK1 control gene expression in Ras-active lung cancer cells, we performed gene profiling experiments to analyze the transcriptomes from control, si-Med23, or si-Elk1 A549 cells.
2013-08-31 | GSE40517 | GEO
Project description:Mediator complex is an integrative hub for transcriptional regulation. Here we show that Mediator regulates alternative mRNA processing via its Med23 subunit. Combining tandem affinity purification and mass spectrometry, we identified a number of mRNA processing factors that bind to a soluble recombinant Mediator subunit MED23 but not to several other Mediator components. One of these factors, hnRNP L, specifically interacts with MED23 in vitro and in vivo. Consistently, Mediator partially colocalizes with hnRNP L and the splicing machinery in the cell. Functionally Med23 regulates a subset of hnRNP L-targeted alternative splicing (AS) and alternative cleavage and polyadenylation (APA) events as shown by minigene reporters and exon array analysis. ChIP-seq analysis revealed that Med23 can regulate hnRNP L occupancy at their co-regulated genes. Taken together, these results demonstrate a crosstalk between Mediator and the splicing machinery, suggesting a novel mechanism for coupling mRNA processing to transcription.
2012-02-24 | GSE33771 | GEO
Project description:Mediator complex is an integrative hub for transcriptional regulation. Here we show that Mediator regulates alternative mRNA processing via its Med23 subunit. Combining tandem affinity purification and mass spectrometry, we identified a number of mRNA processing factors that bind to a soluble recombinant Mediator subunit MED23 but not to several other Mediator components. One of these factors, hnRNP L, specifically interacts with MED23 in vitro and in vivo. Consistently, Mediator partially colocalizes with hnRNP L and the splicing machinery in the cell. Functionally Med23 regulates a subset of hnRNP L-targeted alternative splicing (AS) and alternative cleavage and polyadenylation (APA) events as shown by minigene reporters and exon array analysis. ChIP-seq analysis revealed that Med23 can regulate hnRNP L occupancy at their co-regulated genes. Taken together, these results demonstrate a crosstalk between Mediator and the splicing machinery, suggesting a novel mechanism for coupling mRNA processing to transcription.
2012-02-24 | GSE33887 | GEO
Project description:We sought to find molecular signatures of the SGZ cell types, and to characterize the molecular pathways and transcription factor cascades that define the neurogenic niche. We used laser capture microdissection and DNA microarrays to profile gene expression in the inner (SGZ) and outer portions of the dentate gyrus (DG). Since the vast majority of the cells in the DG are mature granule cells, we compared the expression of the inner and outer portions to reveal molecular markers for the less numerous populations of the SGZ. This data set is part of a larger study assessing conserved molecular signatures of neurogenesis in the hippocampal subgranular zone of rodents and primates. Using a combination of selective SGZ transcriptional profiling with laser microdissection and DNA microarrays as well as in situ hybridization (ISH), we developed an extensive molecular characterization of the mouse SGZ, identifying 367 genes enriched in the SGZ compared to mature granule neurons. These genes displayed a wide range of cellular expression patterns reflecting the cellular milieu of the SGZ, including progenitor and dividing cells, immature granule cells, astrocytes, oligodendrocytes, and GABAergic interneurons. We next used a comparable microarray data set in rhesus monkey that profiled the SGZ across postnatal development to identify genes related to developmentally regulated granule cell neurogenesis. The rhesus monkey SGZ showed highly significant similarity to mouse, whereas network analysis of these data identified SGZ-enriched gene sets with different temporal profiles reflecting differential time-courses for maturation of glia and granule neurons. One neurogenesis-related gene network showed a steady decrease in expression across postnatal rhesus development from birth to adulthood. This temporal pattern is highly correlated with the number of proliferating cells in the dentate gyrus, and the neurogenic transcription factors Sox4 and Sox11 are central hub genes for this gene network. A number of the genes in this network showed a similar postnatal downregulation in mouse, suggesting a general conservation of molecular mechanisms underlying developmental and adult neurogenesis in rodents and primates. Primate data available at: http://www.blueprintnhpatlas.org/ Brains from 10- to 11-week-old C57BL/6 male mice housed in three conditions (no running, 4 days of running, 30 days of running) were sectioned and the dentate gyrus was isolated. For each brain, the inner granule cell layer (containing the subgranular zone) and outer GCL were separated using laser capture microdissection, and RNA from each region was collected and processed as described in the protocols.
2013-12-04 | E-GEOD-39697 | biostudies-arrayexpress