Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA288804 | ENA |
REPOSITORIES: ENA
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Project description:Gamma-herpesviruses encode a cytoplasmic mRNA-targeting endonuclease, termed SOX, that cleaves the majority of mRNAs within a cell. Cleaved fragments are subsequently degraded by the cellular mRNA degradation machinery. Here, we reveal that mammalian cells respond to this widespread cytoplasmic mRNA decay by altering levels of RNA polymerase II (RNAPII) transcription in the nucleus. Measurements of both RNAPII recruitment to promoters and nascent mRNA synthesis revealed that the majority of affected genes are transcriptionally repressed in SOX-expressing cells. The transcriptional feedback does not occur in response to the initial endonuclease-induced cleavage, but instead to degradation of the cleaved fragments by cellular exonucleases. In particular, Xrn1 catalytic activity is required for transcriptional repression. Notably, viral mRNA transcription escapes decay-induced repression, and this escape requires Xrn1. Collectively, these results indicate that mRNA decay rates impact transcription in mammalian cells, and that gamma-herpesviruses have incorporated this feedback mechanism into their own gene expression strategy. NIH 3T3 cells were mock, WT, or ∆HS infected with MHV68 in duplicate and 4sU-labeled RNA isolated. 4sU-labeled RNA was submitted for sequencing and reads aligned to the mouse genome or MHV68 viral genome. Differential cellular gene expression was determined between mock and WT infected, mock and ∆HS infected, as well as differential viral gene expression between WT and ∆HS.
2015-07-23 | E-GEOD-70481 | biostudies-arrayexpress
Project description:Gamma-herpesviruses encode a cytoplasmic mRNA-targeting endonuclease, termed SOX, that cleaves the majority of mRNAs within a cell. Cleaved fragments are subsequently degraded by the cellular mRNA degradation machinery. Here, we reveal that mammalian cells respond to this widespread cytoplasmic mRNA decay by altering levels of RNA polymerase II (RNAPII) transcription in the nucleus. Measurements of both RNAPII recruitment to promoters and nascent mRNA synthesis revealed that the majority of affected genes are transcriptionally repressed in SOX-expressing cells. The transcriptional feedback does not occur in response to the initial endonuclease-induced cleavage, but instead to degradation of the cleaved fragments by cellular exonucleases. In particular, Xrn1 catalytic activity is required for transcriptional repression. Notably, viral mRNA transcription escapes decay-induced repression, and this escape requires Xrn1. Collectively, these results indicate that mRNA decay rates impact transcription in mammalian cells, and that gamma-herpesviruses have incorporated this feedback mechanism into their own gene expression strategy.
2015-07-23 | GSE70481 | GEO
Project description:(I am not the first author of the paper who contributed to the experimental data, I did the modeling)
Bistable switches and oscillators have long been considered key mechanisms underlying cell fate decisions and pattern formation in biology. Previous studies of these dynamical behaviors focused on regulatory networks with intuitive feedback loops. It was therefore unclear whether other common biochemical reactions can act as bistable switches or oscillators crucial for cellular and physiological dynamics. In this work, we used mass-action-based models to show that elementary production, degradation and binding reactions involving as few as two RNA species (e.g.an mRNA and a microRNA) can generate bistability and oscillation. We showed that both bistability and oscillation depend on cooperativity of two microRNA binding sites on the mRNA. We therefore termed our model the two-site mRNA-microRNA (MMI2) model. Remarkably, the network structure of the MMI2 model does not have any explicit feedback loop. We estimated that this simple reaction network is applicable to nearly half of human protein-coding genes. Using in vitro and in vivo experiments, we showed the function of a newly proposed MMI2-based switch in governing motor neuron lineage segregation in the spinal cord of mammalian embryos. Our findings reveal a previously underappreciated post-transcriptional mechanism that may have widespread functions in cell fate decisions, oscillatory cell dynamics and tissue patterning. Furthermore, our results challenge the long-standing idea of using intuitive feedback loops to explain bistability and oscillation. In addition to its significance in biology, the MMI2 model enables nontrivial mathematical analysis due to its simplicity. Using algebraic geometry and chemical reaction network theory, we obtained key conditions for bistability of the MMI2 model. These conditions include an inequality that reveals to a hidden feedback loop arising from regulated degradation. For these reasons, we expect that our model will not only provide useful insights into a wide range of problems in cell and developmental biology, but also enable new analytical approaches in systems biology and mathematical biology.
2023-01-18 | MODEL2301180001 | BioModels
Project description:In mammalian cells, widespread acceleration of cytoplasmic mRNA degradation is linked to impaired RNA polymerase II (Pol II) transcription. This mRNA decay-induced transcriptional repression occurs during infection with gammaherpesviruses including Kaposi’s sarcoma associated herpesvirus (KSHV) and murine gammaherpesvirus 68 (MHV68), which encode an mRNA endonuclease that initiates widespread RNA decay. Here, we show that MHV68-induced mRNA decay leads to a genome-wide reduction of Pol II occupancy at mammalian promoters. Viral genes, despite the fact that they require Pol II for transcription, escape this transcriptional repression. Protection is not governed by viral promoter sequences; instead, location on the viral genome is both necessary and sufficient to escape the transcriptional repression effects of mRNA decay. We hypothesize that the ability to escape from transcriptional repression is linked to the localization of viral DNA in replication compartments, providing a means for these viruses to counteract decay-induced viral transcript loss.
2019-12-10 | PXD015786 | Pride
Project description:The mammalian circadian clock involves a transcriptional feedback loop in which CLOCK and BMAL1 activate the Period and Cryptochrome genes, which then feedback and repress their own transcription. We have interrogated the transcriptional architecture of the circadian transcriptional regulatory loop on a genome scale in mouse liver and find a stereotyped, time-dependent pattern of transcription factor binding, RNA polymerase II (RNAPII) recruitment, RNA expression and chromatin states. We find that the circadian transcriptional cycle of the clock consists of three distinct phases M-bM-^@M-^T a poised state, a coordinated de novo transcriptional activation state, and a repressed state. Interestingly only 22% of mRNA cycling genes are driven by de novo transcription, suggesting that both transcriptional and post-transcriptional mechanisms underlie the mammalian circadian clock. We also find that circadian modulation of RNAPII recruitment and chromatin remodeling occurs on a genome-wide scale far greater than that seen previously by gene expression profiling. Examination of whole transcriptome every 4hr during the circadian cycle in mouse liver
2012-08-31 | E-GEOD-39978 | biostudies-arrayexpress
Project description:The mammalian circadian clock involves a transcriptional feedback loop in which CLOCK and BMAL1 activate the Period and Cryptochrome genes, which then feedback and repress their own transcription. We have interrogated the transcriptional architecture of the circadian transcriptional regulatory loop on a genome scale in mouse liver and find a stereotyped, time-dependent pattern of transcription factor binding, RNA polymerase II (RNAPII) recruitment, RNA expression and chromatin states. We find that the circadian transcriptional cycle of the clock consists of three distinct phases - a poised state, a coordinated de novo transcriptional activation state, and a repressed state. Interestingly only 22% of mRNA cycling genes are driven by de novo transcription, suggesting that both transcriptional and post-transcriptional mechanisms underlie the mammalian circadian clock. We also find that circadian modulation of RNAPII recruitment and chromatin remodeling occurs on a genome-wide scale far greater than that seen previously by gene expression profiling. Examination of 9 transcriptional regulators, 2 RNAPII and 6 histone modifications every 4hr during the circadian cycle in mouse liver
2012-08-31 | E-GEOD-39977 | biostudies-arrayexpress
Project description:Messenger RNAs are regulated by a variety of degradation mechanisms in mammalian cells. In the canonical animal microRNA pathway, microRNAs in complex with Argonaute proteins bind to many mRNA targets with imperfect complementarity, leading to degradation of the mRNA through the regular decay machinery. The ancestral “slicer” endonuclease activity of Argonaute2 itself, which requires more extensive complementarity with the target RNA, is not used in this pathway, and has only been observed in two microRNA-guided cases. Nevertheless, the cleavage capacity of mammalian Ago2 is conserved and essential for viability. Here, we assess the endonucleolytic function of Ago2 and other nucleases by identifying cleavage products retaining 5`-phosphate groups in mouse ES cells on a transcriptome-wide scale. We detect a significant signature of Ago2-dependent cleavage events and validate several targets. Unexpectedly, a broader class of Ago2-independent cleavage sites is also observed, indicating participation of additional nucleases in this mode of mRNA regulation. Within this class, we identify a cohort of Drosha-dependent mRNA cleavage events, including one in the Dgcr8 mRNA, that functionally regulate mRNA levels in mES cells. Together, these results highlight the underappreciated role of endonucleolytic cleavage in controlling mRNA fates in mammals. Global 5`-phosphate-dependent RACE in WT, Ago2-KO and Drosha-excised mouse ES cells and human 293S cells
2010-06-25 | E-GEOD-21975 | biostudies-arrayexpress
Project description:The mammalian circadian clock involves a transcriptional feedback loop in which CLOCK and BMAL1 activate the Period and Cryptochrome genes, which then feedback and repress their own transcription. We have interrogated the transcriptional architecture of the circadian transcriptional regulatory loop on a genome scale in mouse liver and find a stereotyped, time-dependent pattern of transcription factor binding, RNA polymerase II (RNAPII) recruitment, RNA expression and chromatin states. We find that the circadian transcriptional cycle of the clock consists of three distinct phases - a poised state, a coordinated de novo transcriptional activation state, and a repressed state. Interestingly only 22% of mRNA cycling genes are driven by de novo transcription, suggesting that both transcriptional and post-transcriptional mechanisms underlie the mammalian circadian clock. We also find that circadian modulation of RNAPII recruitment and chromatin remodeling occurs on a genome-wide scale far greater than that seen previously by gene expression profiling.
2012-08-31 | GSE39977 | GEO
Project description:The mammalian circadian clock involves a transcriptional feedback loop in which CLOCK and BMAL1 activate the Period and Cryptochrome genes, which then feedback and repress their own transcription. We have interrogated the transcriptional architecture of the circadian transcriptional regulatory loop on a genome scale in mouse liver and find a stereotyped, time-dependent pattern of transcription factor binding, RNA polymerase II (RNAPII) recruitment, RNA expression and chromatin states. We find that the circadian transcriptional cycle of the clock consists of three distinct phases — a poised state, a coordinated de novo transcriptional activation state, and a repressed state. Interestingly only 22% of mRNA cycling genes are driven by de novo transcription, suggesting that both transcriptional and post-transcriptional mechanisms underlie the mammalian circadian clock. We also find that circadian modulation of RNAPII recruitment and chromatin remodeling occurs on a genome-wide scale far greater than that seen previously by gene expression profiling.
2012-08-31 | GSE39978 | GEO
Project description:Messenger RNAs are regulated by a variety of degradation mechanisms in mammalian cells. In the canonical animal microRNA pathway, microRNAs in complex with Argonaute proteins bind to many mRNA targets with imperfect complementarity, leading to degradation of the mRNA through the regular decay machinery. The ancestral “slicer” endonuclease activity of Argonaute2 itself, which requires more extensive complementarity with the target RNA, is not used in this pathway, and has only been observed in two microRNA-guided cases. Nevertheless, the cleavage capacity of mammalian Ago2 is conserved and essential for viability. Here, we assess the endonucleolytic function of Ago2 and other nucleases by identifying cleavage products retaining 5`-phosphate groups in mouse ES cells on a transcriptome-wide scale. We detect a significant signature of Ago2-dependent cleavage events and validate several targets. Unexpectedly, a broader class of Ago2-independent cleavage sites is also observed, indicating participation of additional nucleases in this mode of mRNA regulation. Within this class, we identify a cohort of Drosha-dependent mRNA cleavage events, including one in the Dgcr8 mRNA, that functionally regulate mRNA levels in mES cells. Together, these results highlight the underappreciated role of endonucleolytic cleavage in controlling mRNA fates in mammals.
2010-06-25 | GSE21975 | GEO