The transcriptional response to MESH1 silencing
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE135358 | GEO | 2022/08/31
REPOSITORIES: GEO
Similar Datasets
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: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: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: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:The gene encoding the conserved bacterial G protein CgtA (Obg) is essential for viability in every organism in which it has been studied. CgtA has been reported to be involved in several diverse bacterial functions, including ribosome assembly, DNA repair, sporulation and morphological development. However, none of these functions have been identified as essential. Here we show that depletion of CgtA in Vibrio cholerae causes global changes in gene expression that are consistent with induction of a classical low nutrient stress response or “stringent” response. We show that depletion of CgtA leads to increased ppGpp levels which correlates with induction of the global stress response and cessation of growth. The enzyme RelA is responsible for synthesis of the alarmone ppGpp during the stringent response. We show that CgtA is no longer essential in a relA deletion mutant and thus conclude that the essentiality of CgtA is directly linked to its ability to affect ppGpp levels. The enzyme SpoT degrades ppGpp and here we show that SpoT is essential in a RelA+ CgtA+ background but not in a relA deletion mutant. We also confirmed that CgtA interacts with SpoT in a two-hybrid assay. We suggest that the essential function of CgtA is a repressor of the stringent response, and acts by regulating SpoT activity to maintain low ppGpp levels when bacteria are growing in a nutrient rich environment. This SuperSeries is composed of the SubSeries listed below.
2006-12-28 | GSE6618 | GEO
Project description:SpoT is an Rsh (Rel / Spo homolog) protein, which synthesizes the alarmone ppGpp in response to starvation. This experiment is quantifying transcription in two Caulobacter strains after 5 minutes of glucose starvation: one strain is wild-type CB15N (NA1000); the other strain is NA1000 which has a chromosomal in-frame deletion of the spoT gene. The wild-type strain can synthesize the alarmone ppGpp in response to starvation and the spoT null strain cannot. Both strains were cultured in M2 defined medium with glucose as the sole carbon source, and then washed and incubated in M2 medium lacking glucose for 5 minutes before RNA isolation.
2011-05-01 | GSE21206 | GEO
Project description:SpoT is an Rsh (Rel / Spo homolog) protein, which synthesizes the alarmone ppGpp in response to starvation. This experiment is quantifying transcription in two Caulobacter strains after 5 minutes of glucose starvation: one strain is wild-type CB15N (NA1000); the other strain is NA1000 which has a chromosomal in-frame deletion of the spoT gene. The wild-type strain can synthesize the alarmone ppGpp in response to starvation and the spoT null strain cannot. Both strains were cultured in M2 defined medium with glucose as the sole carbon source, and then washed and incubated in M2 medium lacking glucose for 5 minutes before RNA isolation. Triplicate cultures of: 1) C. crescentus strain CB15N , and 2) CB15N ?SpoT, cultured in M2-glucose media, then starved for glucose for 5 minutes.
2011-05-01 | E-GEOD-21206 | biostudies-arrayexpress
Project description:The production of (p)ppGpp by Streptococcus mutans UA159 is catalyzed by three gene products, RelA, RelP and RelQ. Here, we investigate the role of the RelA (Rel) homologue of S. mutans in the stringent response and in global control of gene expression. RelA of S. mutans was shown to synthesize pppGpp in vitro from GTP and ATP in the absence of added ribosomes, as well as in vivo in an E. coli relA-spoT mutant. Mupirocin (MUP) was shown to induce high levels of (p)ppGpp production in S. mutans in a relA-dependent manner, with a concommitant reduction in GTP pools. Keywords: (p)ppGpp, nutrient starvation, biofilm, virulence, stress
2007-11-14 | GSE9382 | GEO
Project description:Here, B. subtilis was used as a model organism to investigate how cells respond and adapt to proteotoxic stress conditions. Our experiments suggested that the stringent response, caused by raised levels of the (p)ppGpp alarmone, plays a role during thermotolerance development and the heat shock response. Accordingly, our experiments revealed a rapid increase of cellular (p)ppGpp levels upon heat shock as well as salt- and oxidative stress. Strains lacking (p)ppGpp exhibited increased stress sensitivity, while raised (p)ppGpp levels conferred increased stress tolerance to heat- and oxidative stress. During thermotolerance development, stress response genes were highly up-regulated together with a concurrent transcriptional down-regulation of the rRNA, which was influenced by the second messenger (p)ppGpp and the transcription factor Spx. Remarkably, we observed that (p)ppGpp appeared to control the cellular translational capacity and that during heat stress the raised cellular levels of the alarmone were able to curb the rate of protein synthesis. Furthermore, (p)ppGpp controls the heat-induced expression of Hpf and thus the formation of translationally inactive 100S disomes. These results indicate that B. subtilis cells respond to heat-mediated protein unfolding and aggregation, not only by raising the cellular repair capacity, but also by decreasing translation involving (p)ppGpp mediated stringent response to concurrently reduce the protein load for the cellular protein quality control system.
2020-03-09 | PXD015416 | Pride
Project description:Transcriptional profiles of wildtype and mutant strains bt0700 and bt0700 bt3998 (ppGpp0) of human gut commensal B. thetaiotaomicron were collected to investigate the relevance of the stringent response mediated by the alarmone (p)ppGpp for growth and survival in three different conditions. RNAseq samples were taken during growth in glucose minimal medium, after 1h of carbon starvation, and after 6 days of monocolonizing germ-free mice (from cecum material).
2018-07-04 | E-MTAB-6412 | biostudies-arrayexpress