Integrator is a genome-wide attenuator of non-productive transcription
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA637642 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11938100.fastq.gz | Fastqsanger.gz | |||
| SRR11938101.fastq.gz | Fastqsanger.gz | |||
| SRR11938102.fastq.gz | Fastqsanger.gz | |||
| SRR11938103.fastq.gz | Fastqsanger.gz | |||
| SRR11938104.fastq.gz | Fastqsanger.gz |
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Project description:Termination of RNA polymerase II (RNAPII) transcription in metazoans relies largely on the Cleavage and Polyadenylation (CPA) and Integrator (INT) complexes originally found to act at the ends of protein-coding and snRNA genes, respectively. Here we monitor CPA- and INT-dependent termination activities genome-wide, including at thousands of previously unannotated transcription units (TUs), producing unstable RNA. We verify the global activity of CPA, occurring at pA sites indiscriminately of their positioning relative to the TU promoter. We also identify a global activity of INT, which is, however, largely sequence-independent and restricted to a ~3 kb promoter-proximal region. Our analyses suggest two functions of genome-wide INT activity; it dampens transcriptional output from weak promoters and it provides quality-control of RNAPII complexes that are unfavorably configured for transcriptional elongation. We suggest that the function of INT in stable snRNA production is an exception from its general cellular role, the attenuation of non-productive transcription.
2021-01-03 | GSE151919 | GEO
Project description:The decision between productive elongation and premature termination of promoter-proximal RNA polymerase II (RNAPII) is fundamental to metazoan gene regulation. Integrator and Restrictor complexes are implicated in promoter-proximal termination, but why metazoans utilise two complexes and how they are coordinated is unknown. Here, we show that Integrator and Restrictor sequentially and non-redundantly monitor distinct early steps of transcription. Integrator predominantly engages paused RNAPII to trigger premature termination, which can be prevented by cyclin-dependent kinase 7/9 activity. Crucially, we reveal a previously unrecognised and universal checkpoint imposed by Restrictor after promoter-proximal pausing. This restriction zone presents an additional opportunity to verify RNAPII. Progression through this second checkpoint requires U1 small nuclear ribonucleoprotein (snRNP), which antagonises Integrator and Restrictor in a U1-70K dependent manner. These findings reveal the principles of a sequential validation mechanism governing the balance between productive and attenuated transcription, rationalising the necessity of Integrator and Restrictor complexes in metazoans.
2025-10-17 | GSE297602 | GEO
Project description:The decision between productive elongation and premature termination of promoter-proximal RNA polymerase II (RNAPII) is fundamental to metazoan gene regulation. Integrator and Restrictor complexes are implicated in promoter-proximal termination, but why metazoans utilise two complexes and how they are coordinated is unknown. Here, we show that Integrator and Restrictor sequentially and non-redundantly monitor distinct early steps of transcription. Integrator predominantly engages paused RNAPII to trigger premature termination, which can be prevented by cyclin-dependent kinase 7/9 activity. Crucially, we reveal a previously unrecognised and universal checkpoint imposed by Restrictor after promoter-proximal pausing. This restriction zone presents an additional opportunity to verify RNAPII. Progression through this second checkpoint requires U1 small nuclear ribonucleoprotein (snRNP), which antagonises Integrator and Restrictor in a U1-70K dependent manner. These findings reveal the principles of a sequential validation mechanism governing the balance between productive and attenuated transcription, rationalising the necessity of Integrator and Restrictor complexes in metazoans.
2025-10-17 | GSE297599 | GEO
Project description:The decision between productive elongation and premature termination of promoter-proximal RNA polymerase II (RNAPII) is fundamental to metazoan gene regulation. Integrator and Restrictor complexes are implicated in promoter-proximal termination, but why metazoans utilise two complexes and how they are coordinated is unknown. Here, we show that Integrator and Restrictor sequentially and non-redundantly monitor distinct early steps of transcription. Integrator predominantly engages paused RNAPII to trigger premature termination, which can be prevented by cyclin-dependent kinase 7/9 activity. Crucially, we reveal a previously unrecognised and universal checkpoint imposed by Restrictor after promoter-proximal pausing. This restriction zone presents an additional opportunity to verify RNAPII. Progression through this second checkpoint requires U1 small nuclear ribonucleoprotein (snRNP), which antagonises Integrator and Restrictor in a U1-70K dependent manner. These findings reveal the principles of a sequential validation mechanism governing the balance between productive and attenuated transcription, rationalising the necessity of Integrator and Restrictor complexes in metazoans.
2025-10-17 | GSE297595 | GEO
Project description:The decision between productive elongation and premature termination of promoter-proximal RNA polymerase II (RNAPII) is fundamental to metazoan gene regulation. Integrator and Restrictor complexes are implicated in promoter-proximal termination, but why metazoans utilise two complexes and how they are coordinated is unknown. Here, we show that Integrator and Restrictor sequentially and non-redundantly monitor distinct early steps of transcription. Integrator predominantly engages paused RNAPII to trigger premature termination, which can be prevented by cyclin-dependent kinase 7/9 activity. Crucially, we reveal a previously unrecognised and universal checkpoint imposed by Restrictor after promoter-proximal pausing. This restriction zone presents an additional opportunity to verify RNAPII. Progression through this second checkpoint requires U1 small nuclear ribonucleoprotein (snRNP), which antagonises Integrator and Restrictor in a U1-70K dependent manner. These findings reveal the principles of a sequential validation mechanism governing the balance between productive and attenuated transcription, rationalising the necessity of Integrator and Restrictor complexes in metazoans.
2025-10-17 | GSE297604 | GEO
Project description:The decision between productive elongation and premature termination of promoter-proximal RNA polymerase II (RNAPII) is fundamental to metazoan gene regulation. Integrator and Restrictor complexes are implicated in promoter-proximal termination, but why metazoans utilise two complexes and how they are coordinated is unknown. Here, we show that Integrator and Restrictor sequentially and non-redundantly monitor distinct early steps of transcription. Integrator predominantly engages paused RNAPII to trigger premature termination, which can be prevented by cyclin-dependent kinase 7/9 activity. Crucially, we reveal a previously unrecognised and universal checkpoint imposed by Restrictor after promoter-proximal pausing. This restriction zone presents an additional opportunity to verify RNAPII. Progression through this second checkpoint requires U1 small nuclear ribonucleoprotein (snRNP), which antagonises Integrator and Restrictor in a U1-70K dependent manner. These findings reveal the principles of a sequential validation mechanism governing the balance between productive and attenuated transcription, rationalising the necessity of Integrator and Restrictor complexes in metazoans.
2025-10-17 | GSE297603 | GEO
Project description:Efficient release of promoter-proximally paused Pol II into productive elongation is essential for gene expression. Recently, we reported that the Integrator complex can bind paused Pol II and drive premature transcription termination, potently attenuating the activity of target genes. Premature termination requires RNA cleavage by the endonuclease subunit of Integrator, but the roles of other Integrator subunits in gene regulation have yet to be elucidated. Here, we report that Integrator subunit 8 (IntS8) is critical for transcription repression through its association with Protein Phosphatase 2A (PP2A). We find that Integrator-bound PP2A dephosphorylates the Pol II C-terminal domain and Spt5, and prevents the transition to productive elongation. Blocking PP2A association with Integrator thus stimulates pause release and gene activation. These results reveal a second catalytic function associated with Integrator-mediated transcription termination, and suggest a new model for the control of productive elongation involving active competition between transcriptional kinases and phosphatases.
2020-10-06 | GSE150844 | GEO
Project description:The transition of RNA polymerase II (Pol II) from initiation to productive elongation is a central, regulated step in metazoan gene expression. At many genes, Pol II pauses stably in early elongation, remaining engaged with the 25-60 nucleotide-long nascent RNA for many minutes while awaiting signals for release into the gene body. However, a number of genes display highly unstable promoter Pol II, suggesting that paused polymerase terminates transcription at these promoters and releases a short, non-functional RNA. Here, we investigate the mechanisms driving Pol II instability and discover that the Integrator complex targets paused Pol II and terminates transcription at selected genes. Specifically, Integrator utilizes its RNA endonuclease activity to cleave nascent RNA and destabilize elongating polymerase. Our findings uncover a previously unappreciated mechanism of metazoan gene repression, wherein promoter paused Pol II is prevented from entering productive elongation through regulated termination.
2019-11-27 | GSE114467 | GEO
Project description:The RNA-binding protein RBP33 dampens non-productive transcription in trypanosomes
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Project description:Cellular homeostasis requires transcriptional outputs to be coordinated, and many events post transcription initiation can dictate the levels and functions of mature transcripts. To systematically identify regulators of inducible gene expression, we performed high-throughput RNAi screening of the Drosophila Metallothionein A (MtnA) promoter. This revealed that the Integrator complex, which has a well-established role in 3' end processing of small nuclear RNAs (snRNAs), attenuates MtnA transcription during copper stress. Integrator complex subunit 11 (IntS11) endonucleolytically cleaves MtnA transcripts, resulting in premature transcription termination and degradation of the nascent RNAs by the RNA exosome, a complex also identified in the screen. Using RNA-seq, we then identified >400 additional Drosophila protein-coding genes whose expression increases upon Integrator depletion. We focused on a subset of these genes and confirmed that Integrator is bound to their 5' ends and negatively regulates their transcription via IntS11 endonuclease activity. Many non-catalytic Integrator subunits, which are largely dispensable for snRNA processing, also have regulatory roles at these protein-coding genes, possibly by controlling Integrator recruitment or RNA polymerase II dynamics. Altogether, our results suggest that attenuation via Integrator cleavage limits production of many full-length mRNAs, allowing precise control of transcription outputs.
2019-09-12 | GSE136150 | GEO