Integrative analysis of RNA Polymerase II and transcriptional dynamics upon Myc activation
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ABSTRACT:
PROVIDER: PRJNA385023 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5493410.fastq.gz | Fastqsanger.gz | |||
| SRR5493420.fastq.gz | Fastqsanger.gz | |||
| SRR5493430.fastq.gz | Fastqsanger.gz | |||
| SRR5493430_1.fastq.gz | Fastqsanger.gz | |||
| SRR5493430_2.fastq.gz | Fastqsanger.gz |
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Project description:Over-expression of the Myc transcription factor causes its widespread interaction with regulatory domains in the genome, but leads to the up- and down-regulation of discrete sets of genes. The molecular determinants of these selective transcriptional responses remain elusive. Here, we present an integrated time-course analysis of transcription and mRNA dynamics following Myc activation in proliferating mouse fibroblasts, based on chromatin immunoprecipitation, metabolic labeling of newly synthesized RNA, extensive sequencing and mathematical modeling. Transcriptional activation correlated with the highest increases in Myc binding at promoters. Repression followed a reciprocal scenario, with the lowest gains in Myc binding. Altogether, the relative abundance (henceforth, “share”) of Myc at promoters was the strongest predictor of transcriptional responses in diverse cell types, predominating over Myc’s association with the co-repressor Miz1. Myc activation elicited immediate loading of RNAPII at activated promoters, followed by increases in pause-release5, while repressed promoters showed opposite effects. Gains and losses in RNAPII loading were proportional to the changes in the Myc share, suggesting that repression by Myc may be largely indirect, owing - at least in part - to competition for limiting amounts of RNAPII. Secondary to the changes in RNAPII loading, the dynamics of elongation and pre-mRNA processing were also rapidly altered at Myc regulated genes, leading to the transient accumulation of partially or aberrantly processed mRNAs. Altogether, our results shed light on how over-expressed Myc alters the various phases of the RNAPII cycle and the resulting transcriptional response.
2017-08-23 | GSE98420 | GEO
Project description:Overexpression of the MYC transcription factor causes its widespread interaction with regulatory elements in the genome but leads to the up- and down-regulation of discrete sets of genes. The molecular determinants of these selective transcriptional responses remain elusive. Here, we present an integrated time-course analysis of transcription and mRNA dynamics following MYC activation in proliferating mouse fibroblasts, based on chromatin immunoprecipitation, metabolic labeling of newly synthesized RNA, extensive sequencing, and mathematical modeling. Transcriptional activation correlated with the highest increases in MYC binding at promoters. Repression followed a reciprocal scenario, with the lowest gains in MYC binding. Altogether, the relative abundance (henceforth, "share") of MYC at promoters was the strongest predictor of transcriptional responses in diverse cell types, predominating over MYC's association with the corepressor ZBTB17 (also known as MIZ1). MYC activation elicited immediate loading of RNA polymerase II (RNAPII) at activated promoters, followed by increases in pause-release, while repressed promoters showed opposite effects. Gains and losses in RNAPII loading were proportional to the changes in the MYC share, suggesting that repression by MYC may be partly indirect, owing to competition for limiting amounts of RNAPII. Secondary to the changes in RNAPII loading, the dynamics of elongation and pre-mRNA processing were also rapidly altered at MYC regulated genes, leading to the transient accumulation of partially or aberrantly processed mRNAs. Altogether, our results shed light on how overexpressed MYC alters the various phases of the RNAPII cycle and the resulting transcriptional response.
| S-EPMC5630029 | biostudies-literature
Project description:Over-expression of the Myc transcription factor causes its widespread interaction with regulatory domains in the genome, but leads to the up- and down-regulation of discrete sets of genes. The molecular determinants of these selective transcriptional responses remain elusive. Here, we present an integrated time-course analysis of transcription and mRNA dynamics following Myc activation in proliferating mouse fibroblasts, based on chromatin immunoprecipitation, metabolic labeling of newly synthesized RNA, extensive sequencing and mathematical modeling. Transcriptional activation correlated with the highest increases in Myc binding at promoters. Repression followed a reciprocal scenario, with the lowest gains in Myc binding. Altogether, the relative abundance (henceforth, “share”) of Myc at promoters was the strongest predictor of transcriptional responses in diverse cell types, predominating over Myc’s association with the co-repressor Miz1. Myc activation elicited immediate loading of RNAPII at activated promoters, followed by increases in pause-release5, while repressed promoters showed opposite effects. Gains and losses in RNAPII loading were proportional to the changes in the Myc share, suggesting that repression by Myc may be largely indirect, owing - at least in part - to competition for limiting amounts of RNAPII. Secondary to the changes in RNAPII loading, the dynamics of elongation and pre-mRNA processing were also rapidly altered at Myc regulated genes, leading to the transient accumulation of partially or aberrantly processed mRNAs. Altogether, our results shed light on how over-expressed Myc alters the various phases of the RNAPII cycle and the resulting transcriptional response.
2017-08-23 | GSE98419 | GEO
Project description:Over-expression of the Myc transcription factor causes its widespread interaction with regulatory domains in the genome, but leads to the up- and down-regulation of discrete sets of genes. The molecular determinants of these selective transcriptional responses remain elusive. Here, we present an integrated time-course analysis of transcription and mRNA dynamics following Myc activation in proliferating mouse fibroblasts, based on chromatin immunoprecipitation, metabolic labeling of newly synthesized RNA, extensive sequencing and mathematical modeling. Transcriptional activation correlated with the highest increases in Myc binding at promoters. Repression followed a reciprocal scenario, with the lowest gains in Myc binding. Altogether, the relative abundance (henceforth, “share”) of Myc at promoters was the strongest predictor of transcriptional responses in diverse cell types, predominating over Myc’s association with the co-repressor Miz1. Myc activation elicited immediate loading of RNAPII at activated promoters, followed by increases in pause-release5, while repressed promoters showed opposite effects. Gains and losses in RNAPII loading were proportional to the changes in the Myc share, suggesting that repression by Myc may be largely indirect, owing - at least in part - to competition for limiting amounts of RNAPII. Secondary to the changes in RNAPII loading, the dynamics of elongation and pre-mRNA processing were also rapidly altered at Myc regulated genes, leading to the transient accumulation of partially or aberrantly processed mRNAs. Altogether, our results shed light on how over-expressed Myc alters the various phases of the RNAPII cycle and the resulting transcriptional response.
2017-08-23 | GSE98418 | GEO
Project description:Deregulated expression of MYC enhances glutamine utilization and renders cell survival dependent on glutamine, inducing “glutamine addiction”. Surprisingly, colon cancer cells that express high levels of MYC due to WNT pathway mutations, are not glutamine-addicted but undergo a reversible cell cycle arrest upon glutamine deprivation. We show here that glutamine deprivation suppresses translation of endogenous MYC via the 3’-UTR of the MYC mRNA, enabling escape from apoptosis. This regulation is mediated by glutamine-dependent changes in adenosine nucleotide levels. Glutamine deprivation causes a global reduction in promoter association of RNA Polymerase II (RNAPII) and slows transcriptional elongation. While activation of MYC restores binding of MYC and RNAPII function on most promoters, restoration of elongation is imperfect and activation of MYC in the absence of glutamine causes stalling of RNAPII on multiple genes, correlating with R-loop formation. Stalling of RNAPII and R-loop formation can cause DNA damage, arguing that the MYC 3’-UTR is critical for maintaining genome stability when ribonucleotide levels are low.
2022-02-28 | PXD005829 | Pride
Project description:MYC family proteins are oncogenic transcription factors that can globally affect the function of RNA Polymerase II (RNAPII). The ability of MYC proteins to promote transcription elongation depends on their ubiquitination, but the underlying mechanism and its biological relevance are unknown. Here we show that MYC and the Polymerase II associated factor, PAF1c, interact directly and their function is mutually dependent, since the specific binding of MYC to active promoters depends on PAF1c and, conversely, PAF1c is required for MYC-dependent pause release. Upon binding, PAF1c is rapidly transferred from MYC onto RNAPII and this transfer is driven by the HUWE1 ubiquitin ligase. Both MYC and HUWE1 globally control histone H2B ubiquitylation, which promotes transcriptional elongation and alters chromatin structure for double-strand break repair. Consistently, MYC suppresses the accumulation of double-strand breaks at promoters in response to topoisomerase II inhibition. While depletion of PAF1c has only minor effects on MYC-dependent gene expression, MYC induces rampant transcription-dependent DNA damage in PAF1c-depleted cells. We propose that the HUWE1-dependent transfer of PAF1c from MYC onto RNAPII is critical for absorbing the topological stress accompanied with deregulated and oncogenic transcription.
2021-02-15 | PXD023242 | Pride
Project description:Deregulated expression of MYC enhances glutamine utilization and renders cell survival dependent on an external supply of glutamine, an observation termed “glutamine addiction”. Surprisingly, human colon cancer cells, which express high levels of MYC due to mutations in the WNT pathway, are not glutamine-addicted but undergo a reversible cell cycle arrest upon glutamine deprivation. We show here that glutamine deprivation suppresses endogenous MYC expression via the 3’-UTR of the MYC mRNA, enabling escape from apoptosis. The glutamine-dependent metabolites that mediate this regulation are adenosine nucleotides. Glutamine deprivation causes a global reduction in promoter association of RNA Polymerase II (RNAPII) and reduces the RNAPII traveling ratio, indicative of defects in transcriptional elongation. While RNAPII function is restored by activation of MYC on most genes, restoration of elongation is imperfect and activation of MYC in the absence of glutamine enhances stalling of RNAPII in the body of individual genes, promoting the formation of R-loops. Since stalling of RNAPII and R-loop formation are potential causes of DNA damage, our data argue that the MYC 3’-UTR has a critical role in maintaining genome instability when ribonucleotide levels are low.
2017-04-13 | GSE86556 | GEO
Project description:Lysine-specific demethylase 1 (LSD1) catalyzes the demethylation at H3K4 and H3K9 and is well- known for its role in decommissioning enhancers during mouse embryonic stem cell (ESC) differentiation. However, its role at gene promoters remains poorly understood in ESCs despite their widespread presence at these sites. Here, we report that LSD1 promotes RNA Polymerase II (RNAPII) pausing, a rate-limiting step in transcription regulation, in ESCs. We found that the knockdown of LSD1 preferentially affects genes with higher RNAPII pausing than those with lower pausing. We show that LSD1 knockdown leads to the global reduction in RNAPII pausing and most significantly on the genes bound by LSD1. Next, we demonstrate that the co-localization of LSD1 and MYC, a factor known to regulate pause-release, is associated with the enrichment of other RNAPII pausing factors. Finally, we found that genes co-occupied by LSD1 and MYC are significantly enriched for housekeeping genes that are involved in metabolic processes and depleted of transcription factors compared to those bound only by LSD1. Our integrative analysis reveals a pleiotropic role of LSD1 in promoting RNAPII pausing and in regulating housekeeping programs besides its known role in regulating cell identity programs.
2022-08-16 | GSE173089 | GEO
Project description:During the progression of cardiac hypertrophy, cardiomyocytes accelerate RNA biogenesis to meet increasing metabolic demands under exogenous hypertrophic stimuli. We have elucidated the quantitative kinetics of RNA in c-Myc (Myc)-mediated hypermetabolic analytical model using cultured neonatal rat cardiomyocytes. Chromatin immunoprecipitation and high-throughput sequencing demonstrate that overexpressed Myc binds to a specific set of genes directly in cardiomyocytes and recruits RNA polymerase II to these genes.
2016-07-10 | GSE78934 | GEO
Project description:MYC family proteins are oncogenic transcription factors that can globally affect the function of RNA Polymerase II (RNAPII). The ability of MYC proteins to promote transcription elongation depends on their ubiquitination, but the underlying mechanism and its biological relevance are unknown. Here we show that MYC and the Polymerase II associated factor, PAF1c, interact directly and their function is mutually dependent, since the specific binding of MYC to active promoters depends on PAF1c and, conversely, PAF1c is required for MYC-dependent pause release. Upon binding, PAF1c is rapidly transferred from MYC onto RNAPII and this transfer is driven by the HUWE1 ubiquitin ligase. Both MYC and HUWE1 globally control histone H2B ubiquitylation, which promotes transcriptional elongation and alters chromatin structure for double-strand break repair. Consistently, MYC suppresses the accumulation of double-strand breaks at promoters in response to topoisomerase II inhibition. While depletion of PAF1c has only minor effects on MYC-dependent gene expression, MYC induces rampant transcription-dependent DNA damage in PAF1c-depleted cells. We propose that the HUWE1-dependent transfer of PAF1c from MYC onto RNAPII is critical for absorbing the topological stress accompanied with deregulated and oncogenic transcription.
2021-02-10 | GSE160849 | GEO