Hda1C restricts burst frequency to limit divergent non-coding transcription
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ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE167499 | GEO | 2021/08/02
REPOSITORIES: GEO
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Project description:Hda1C restricts burst frequency to limit divergent non-coding transcription
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Project description:Nucleosome-depleted regions (NDRs) at gene promoters support initiation of RNA polymerase II transcription. Interestingly, transcription often initiates in both directions, resulting in an mRNA and a divergent non-coding (DNC) transcript of unclear purpose. Here, we characterized the genetic architecture and molecular mechanism of DNC transcription in budding yeast. Using high-throughput reverse genetic screens based on quantitative single-cell fluorescence measurements, we identified the Hda1 histone deacetylase complex (Hda1C) as a repressor of DNC transcription. Nascent transcription profiling showed a genome-wide role of Hda1C in repression of DNC transcription. Live-cell imaging of transcription revealed that mutations in the Hda3 subunit increased the frequency of DNC transcription. Hda1C contributed to decreased acetylation of histone H3 in DNC transcription regions, supporting DNC transcription repression by histone deacetylation. Our data support the interpretation that DNC transcription results as a consequence of the NDR-based architecture of eukaryotic promoters, but that it is governed by locus-specific repression to maintain genome fidelity.
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2023-06-01 | E-MTAB-11046 | biostudies-arrayexpress
Project description:Eukaryotic gene transcription is often controlled at the level of RNA polymerase II (Pol II) pausing in the promoter-proximal region. Pausing Pol II limits the frequency of transcription initiation ('pause-initiation limit'), predicting that the pause duration must be decreased for transcriptional activation. To test this prediction, we conduct a genome-wide kinetic analysis of the heat shock response in human cells. We show that the pause-initiation limit restricts transcriptional activation at most genes. Gene activation generally requires the activity of the P-TEFb kinase CDK9, which decreases the duration of Pol II pausing and thereby enables an increase in the productive initiation frequency. The transcription of enhancer elements is generally not pause limited and can be activated without CDK9 activity. Our results define the kinetics of Pol II transcriptional regulation in human cells at all gene classes during a natural transcription response.
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Project description:Gene expression occurs either as an episodic process, characterized by pulsatile bursts, or as a constitutive process, characterized by a Poisson-like accumulation of gene products. It is not clear which mode of gene expression (constitutive versus bursty) predominates across a genome or how transcriptional dynamics are influenced by genomic position and promoter sequence. Here, we use time-lapse fluorescence microscopy to analyze 8,000 individual human genomic loci and find that at virtually all loci, episodic bursting--as opposed to constitutive expression--is the predominant mode of expression. Quantitative analysis of the expression dynamics at these 8,000 loci indicates that both the frequency and size of the transcriptional bursts varies equally across the human genome, independent of promoter sequence. Strikingly, weaker expression loci modulate burst frequency to increase activity, whereas stronger expression loci modulate burst size to increase activity. Transcriptional activators such as trichostatin A (TSA) and tumor necrosis factor ? (TNF) only modulate burst size and frequency along a constrained trend line governed by the promoter. In summary, transcriptional bursting dominates across the human genome, both burst frequency and burst size vary by chromosomal location, and transcriptional activators alter burst frequency and burst size, depending on the expression level of the locus.
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Project description:Many mammalian genes are transcribed during short bursts of variable frequencies and sizes that substantially contribute to cell-to-cell variability. However, which molecular mechanisms determine bursting properties remains unclear. To probe putative mechanisms, we combined temporal analysis of transcription along the circadian cycle with multiple genomic reporter integrations, using both short-lived luciferase live microscopy and single-molecule RNA-FISH. Using the Bmal1 circadian promoter as our model, we observed that rhythmic transcription resulted predominantly from variations in burst frequency, while the genomic position changed the burst size. Thus, burst frequency and size independently modulated Bmal1 transcription. We then found that promoter histone-acetylation level covaried with burst frequency, being greatest at peak expression and lowest at trough expression, while remaining unaffected by the genomic location. In addition, specific deletions of ROR-responsive elements led to constitutively elevated histone acetylation and burst frequency. We then investigated the suggested link between histone acetylation and burst frequency by dCas9p300-targeted modulation of histone acetylation, revealing that acetylation levels influence burst frequency more than burst size. The correlation between acetylation levels at the promoter and burst frequency was also observed in endogenous circadian genes and in embryonic stem cell fate genes. Thus, our data suggest that histone acetylation-mediated control of transcription burst frequency is a common mechanism to control mammalian gene expression.
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Project description:Working memory training has been a hot topic over the last decade. Although studies show benefits in trained and untrained tasks as a function of training, there is an ongoing debate on the efficacy of working memory training. There have been numerous meta-analyses put forth to the field, some finding overall broad transfer effects while others do not. However, discussion of this research typically overlooks specific qualities of the training and transfer tasks. As such, there has been next to no discussion in the literature on what training and transfer tasks features are likely to mediate training outcomes. To address this gap, here, we characterized the broad diversity of features employed in N-back training tasks and outcome measures in published working memory training studies. Extant meta-analyses have not taken into account the diversity of methodology at this level, primarily because there are too few studies using common methods to allow for a robust meta-analysis. We suggest that these limitations preclude strong conclusions from published data. In order to advance research on working memory training, and in particular, N-back training, more studies are needed that systematically compare training features and use common outcome measures to assess transfer effects.
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Project description:We performed a fluorescent reporter based screen to identify factors determining transcriptional directionality from bidirectional promoters that give rise to a coding and a non-coding transcript. Promoters like these are most frequent in many organisms and non-coding transcription from this origin represents a large fraction of total long non-coding transcripts. We applied NET-seq to compare nascent transcription in yeast wild-type and mutations in the three members of the CAF-I complex. This technique avoids the technical issue of co-transcriptional RNA degradation and is a powerful approach to address questions concerning non-coding transcription. We find divergent non-coding transcription to be elevated in CAF-I mutants. One condition, yeast grown in YPD media to mid-log phase. 8 NET-seq libraries are deposited, 2 biological repeats of the wild-type and two biological repeast each of the CAF-I complex member mutants (CAC1, CAC2, CAC3).
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Project description:Eukaryotic gene transcription is often controlled at the level of RNA polymerase II (Pol II) pausing in the promoter-proximal region. Pausing Pol II limits the frequency of transcription initiation (‘pause-initiation limit’), predicting that the pause duration must be decreased for transcriptional activation. To test this prediction, we conducted a genome-wide kinetic analysis of the heat shock response in human cells. We show that the pause-initiation limit restricts transcriptional activation at most genes. Gene activation generally requires the activity of the P-TEFb kinase CDK9, which decreases the duration of Pol II pausing and thereby enables an increase in the productive initiation frequency. The transcription of enhancer elements is generally not pause-limited and can be activated without CDK9 activity. Our results define the kinetics of Pol II transcriptional regulation in human cells at all gene classes during a natural transcription response.
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Project description:This SuperSeries is composed of the SubSeries listed below.
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