TAZ overexpression partially rescued the transcriptomic reprogramming triggered by MESH1 silencing
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PROVIDER: PRJNA558540 | ENA |
REPOSITORIES: ENA
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Project description:TAZ is an important transcriptional co-activator involved in the HIPPO pathway that regulates cell growth, tumorigenesis and organ development and can play as a key mediator in other signaling pathways, such as MESH1-regulated pathways. MESH1 is the human ortholog of spoT that regulates sringent response in bacteria. MESH1 silencing inhibits cell proliferation and triggers a genome-wide transcriptional reprogramming as how spoT works in bacteria, among which TAZ is significantly down-regulated. Therefore, we aim to investigate how much TAZ contributes to the MESH1-regulated gene signature. We performed this microarray restoring TAZ level upon MESH1 silencing and measured the rescue effect. Overall, approximately 30% of the MESH1 regulated genes (up or down-regulated by siMESH1 by at least 2 folds) were rescued by the TAZ overexpression by at least 1.5 folds. Interestingly, a series of cell cycle related genes (RRM1, RRM2,CDK1 and CDC6) were rescued by TAZ restoration, suggesting that TAZ is an important mediator involved in the MESH1-regulated pathway to trigger the downstream tarnscriptomic reprogramming and cell proliferation inhibition. By understanding the mechanisms of MESH1 and its regulated pathways, we may disclose a new target for cancer therapy to regulate cancer cell growth. We used microarrays to detail the coverage of TAZ regulated genes downstream to MESH1 regulated gene signature in H1975 cells.
2022-07-23 | GSE135346 | GEO
Project description:All organisms are constantly exposed to various stresses, necessitating adaptive strategies for survival. In bacteria, the main stress-coping mechanism is the stringent response triggered by the accumulation of “alarmone” (p)ppGpp to arrest proliferation and reprogram transcriptome. While mammalian genomes encode MESH1—the homolog of the (p)ppGpp hydrolase SpoT, current knowledge about its function remains limited. We found MESH1 expression tended to be higher in tumors and associated with poor patient outcomes. Consistently, MESH1 knockdown robustly inhibited proliferation, depleted dNTPs, reduced tumor sphere formation, and retarded xenograft growth. These antitumor phenotypes associated with MESH1 knockdown were accompanied by a significantly altered transcriptome, including the repressed expression of TAZ, a HIPPO coactivator, and proliferative gene. Importantly, TAZ restoration mitigated many anti-growth phenotypes of MESH1 knockdown, including proliferation arrest, reduced sphere formation, tumor growth inhibition, dNTP depletion, and transcriptional changes. Furthermore, TAZ repression was associated with the histone hypo-acetylation at TAZ regulatory loci due to the induction of epigenetic repressors HDAC5 and AHRR. Together, MESH1 knockdown in human cells altered the genome-wide transcriptional patterns and arrested proliferation that mimicked the bacterial stringent response through the epigenetic repression of TAZ expression.
2022-03-12 | GSE147062 | GEO
Project description:MESH1 knockdown triggers proliferation arrest through TAZ repression
| PRJNA612863 | ENA
Project description:All organisms are exposed to various stresses, necessitating adaptive strategies for survival and homeostasis. In bacteria, the main stress-coping mechanism is stringent response triggered by the accumulation of the “alarmone” (p)ppGpp to trigger proliferation arrest and transcriptional reprogramming. Mammalian genomes encode MESH1 —the homologue of the (p)ppGpp hydrolase SpoT, with unknown function. Therefore, we used microarrays to determine the transcriptional response to MESH1 silencing.
2022-08-31 | GSE135358 | GEO
Project description:MESH1 encodes for Metazoan SpoT Homolog 1, which is a homologue of bacterial SpoT that mediates bacterial stringent response. In human cells, we found that MESH1-silencing induces an extensive transcriptional response in clear cell carcinoma cell line RCC4 that partially overlap with mammalian cell integrated stress response (ISR), which ATF4 up-regulation is an essential branch of the response. In this study, the goal is to elucidate the role of ATF4 up-regulation in MESH1-silencing transcriptional response.
2021-07-30 | GSE114128 | GEO
Project description:Nutrient deprivation triggers stringent response in bacteria, allowing rapid reallocation of resources from proliferation toward stress survival. Critical to this process is the accumulation of (p)ppGpp regulated by the RelA/SpoT homologues. While mammalian genomes encode MESH1—the homologue of the bacterial (p)ppGpp hydrolase SpoT, neither (p)ppGpp nor its synthetase has been identified in mammalian cells. Therefore, the function of MESH1 remains a mystery. Here, we report that genetic removal of MESH1 from human cell induce an extensive transcriptional response. The changes are distinct from the canonical unfolding protein response but strongly resemble the bacterial stringent response, which induce cell proliferation arrest, implicating MESH1 in a previously uncharacterized stress response in human cells.
2020-01-26 | GSE114282 | GEO
Project description:All organisms are constantly exposed to various stresses, necessitating adaptive strategies for survival. In bacteria, the main stress-coping mechanism is the stringent response triggered by the accumulation of "alarmone" (p)ppGpp to arrest proliferation and reprogram transcriptome. While mammalian genomes encode MESH1-the homolog of the (p)ppGpp hydrolase SpoT, current knowledge about its function remains limited. We found MESH1 expression tended to be higher in tumors and associated with poor patient outcomes. Consistently, MESH1 knockdown robustly inhibited proliferation, depleted dNTPs, reduced tumor sphere formation, and retarded xenograft growth. These antitumor phenotypes associated with MESH1 knockdown were accompanied by a significantly altered transcriptome, including the repressed expression of TAZ, a HIPPO coactivator, and proliferative gene. Importantly, TAZ restoration mitigated many anti-growth phenotypes of MESH1 knockdown, including proliferation arrest, reduced sphere formation, tumor growth inhibition, dNTP depletion, and transcriptional changes. Furthermore, TAZ repression was associated with the histone hypo-acetylation at TAZ regulatory loci due to the induction of epigenetic repressors HDAC5 and AHRR. Together, MESH1 knockdown in human cells altered the genome-wide transcriptional patterns and arrested proliferation that mimicked the bacterial stringent response through the epigenetic repression of TAZ expression.
| S-EPMC8913805 | biostudies-literature
Project description:The transcriptional response to MESH1 silencing
| PRJNA558557 | ENA
Project description:YAP1 gene fusions have been observed in a subset of paediatric ependymomas. Here we show that, ectopic expression of active nuclear YAP1 (nlsYAP5SA) in ventricular zone neural progenitor cells using conditionally-induced NEX/NeuroD6-Cre is sufficient to drive brain tumour formation in mice. Neuronal differentiation is inhibited in the hippocampus. Deletion of YAP1’s negative regulators LATS1 and LATS2 kinases in NEX-Cre lineage in double conditional knockout mice also generates similar tumours, which are rescued by deletion of YAP1 and its paralog TAZ. YAP1/TAZ-induced mouse tumours display molecular and ultrastructural characteristics of human ependymoma. RNA sequencing and quantitative proteomics of mouse tumours demonstrate similarities to YAP1-fusion induced supratentorial ependymoma. Finally, we find that transcriptional cofactor HOPX is upregulated in mouse models and in human YAP1-fusion induced ependymoma, supporting their similarity. Our results show that uncontrolled YAP1/TAZ activity in neuronal precursor cells leads to ependymoma-like tumours in mice.
2020-05-26 | PXD018131 | Pride
Project description:Transcriptional profile of MESH1-silenced RCC4 cells
| PRJNA470796 | ENA