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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Project description:Hda1C directly binds to actively transcribed regions likely via the interaction with elongating RNA PolII and/or with nascent RNA transcripts. The Arb2 domain of Hda1 is also critical for its binding to chromatin. Interestingly, Hda1C specifically deacetylates histone H4 but not H3 at active genes to suppress nucleosome instability and partially inhibit elongation. In contrast, Hda1C mainly deacetylates histone H3 at inactive genes to delay gene induction.
2019-07-22 | GSE121762 | GEO
Project description:Hda1C directly binds to actively transcribed regions likely via the interaction with elongating RNA PolII and/or with nascent RNA transcripts. The Arb2 domain of Hda1 is also critical for its binding to chromatin. Interestingly, Hda1C specifically deacetylates histone H4 but not H3 at active genes to suppress nucleosome instability and partially inhibit elongation. In contrast, Hda1C mainly deacetylates histone H3 at inactive genes to delay gene induction.
2019-07-22 | GSE121761 | GEO
Project description:In yeast, Hda1 histone deacetylase complex (Hda1C) plays an important role in transcriptional regulation by modulating histone acetylation. We here explored the dynamics of Hda1C binding in nutrient-rich and -starved conditions. Chromatin immunoprecipitation sequencing revealed that starvation alters RNA Pol II and Hda1C binding to coding genes in a highly correlated manner. Interestingly, we discovered RNA Pol II transcription-independent recruitment of Hda1C to intergenic regions, particularly the upstream regulatory sequences (URS) of ribosomal protein (RP) genes, which are enriched with Rap1 binding sites. Under nutrient starvation, Rap1 contributes to the recruitment of Hda1C to these URS regions, where Hda1C deacetylates histones, thereby fine-tuning basal gene expression and delaying RP gene reactivation. Furthermore, Hda1C is also required for RNA Pol I transcription of rRNAs and RNA Pol III transcription of tRNA genes, especially in nutrient-limited conditions. Significantly, Hda1C mutants are sensitive to translation inhibitors and display altered ribosome profiles. Thus, Hda1C may coordinate transcriptional regulation within the nucleus with translation control in the cytoplasm and could be a key regulator of gene expression responses to nutrient stress.
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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 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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