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Integrator endonuclease drives promoter-proximal termination at all RNAPII transcribed loci (PRO-Seq)

ABSTRACT: Pausing of RNA polymerase II (RNAPII) in early elongation is critical for gene regulation. Paused RNAPII can be released into productive elongation by the kinase P-TEFb or targeted for premature termination by the Integrator complex. Integrator comprises endonuclease and phosphatase activities, driving termination through cleavage of nascent RNA and removal of stimulatory phosphorylation. To probe the direct consequences of Integrator activity, we generated a degron system to rapidly deplete the Integrator endonuclease INTS11. Degradation of INTS11 elicits a nearly universal increase in RNAPII escape from promoter regions. However, these RNAPII complexes fail to achieve optimal elongation rates and reveal continued Integrator phosphatase activity. Short transcripts are thus selectively upregulated by INTS11 loss, including many non-coding RNAs, transcription factors and signaling regulators. Together, our data indicate a common function for INTS11 at all RNAPII loci, with differential effects on particular genes, pathways or RNA biotypes reflecting transcript lengths rather than Integrator specificity.

ORGANISM(S): Mus musculus

PROVIDER: GSE200698 | GEO | 2022/10/28

REPOSITORIES: GEO

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Integrator endonuclease drives promoter-proximal termination at all RNAPII transcribed loci (TT-seq)

Project description:Pausing of RNA polymerase II (RNAPII) in early elongation is critical for gene regulation. Paused RNAPII can be released into productive elongation by the kinase P-TEFb or targeted for premature termination by the Integrator complex. Integrator comprises endonuclease and phosphatase activities, driving termination through cleavage of nascent RNA and removal of stimulatory phosphorylation. To probe the direct consequences of Integrator activity, we generated a degron system to rapidly deplete the Integrator endonuclease INTS11. Degradation of INTS11 elicits a nearly universal increase in RNAPII escape from promoter regions. However, these RNAPII complexes fail to achieve optimal elongation rates and reveal continued Integrator phosphatase activity. Short transcripts are thus selectively upregulated by INTS11 loss, including many non-coding RNAs, transcription factors and signaling regulators. Together, our data indicate a common function for INTS11 at all RNAPII loci, with differential effects on particular genes, pathways or RNA biotypes reflecting transcript lengths rather than Integrator specificity.

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The Human Integrator Complex Facilitates Transcriptional Elongation by Endonucleolytic Cleavage of Nascent Transcripts

Project description:Transcription by RNA polymerase II (RNAPII) is pervasive in the human genome. However, the mechanisms controlling transcription at promoters and enhancers remain enigmatic. Here, we demonstrate that Integrator subunit 11 (INTS11), the catalytic subunit of the Integrator complex, regulates transcription at these loci through its endonuclease activity. Promoters of genes require INTS11 to cleave nascent transcripts associated with paused RNAPII and induce their premature termination in the proximity of the +1 nucleosome. The turnover of RNAPII permits the subsequent recruitment of an elongation-competent RNAPII complex, leading to productive elongation. In contrast, enhancers require INTS11 catalysis not to evict paused RNAPII but rather to terminate enhancer RNA transcription beyond the +1 nucleosome. These findings are supported by the differential occupancy of negative elongation factor (NELF), SPT5, and tyrosine-1-phosphorylated RNAPII. This study elucidates the role of Integrator in mediating transcriptional elongation at human promoters through the endonucleolytic cleavage of nascent transcripts and the dynamic turnover of RNAPII.

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Integrator enforces the fidelity of transcriptional termination at protein-coding genes

Project description:Integrator regulates the 3’-end processing and termination of multiple classes of noncoding RNAs. Depletion of INTS11, the catalytic subunit of Integrator, or ectopic expression of its catalytic dead enzyme impairs the 3’-end processing and termination of a set of protein coding transcripts termed Integrator-regulated termination (IRT) genes. This defect is manifested by increased RNA polymerase II (RNAPII) readthrough and occupancy of serine-2 phosphorylated RNAPII, de-novo trimethylation of lysine 36 on histone H3, and a compensatory elevation of the cleavage and polyadenylation (CPA) complex in the downstream regions. 3’-RNA-sequnecing reveals that proximal polyadenylation site usage relies on the endonuclease activity of INTS11. The DNA sequence encompassing the transcription end sites of IRT genes feature downstream polyadenylation motifs and an enrichment of GC content that permits the formation of secondary structures within the 3’UTR. Taken together, this study identifies a subset of protein-coding transcripts whose 3’-end processing requires the Integrator complex.

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Integrator Recruits Protein Phosphatase 2A to Prevent Pause Release and Enable Transcription Termination

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.

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Integrator complex regulates NELF-mediated RNA Polymerase II pause/release and processivity at coding genes [RNA-seq]

Project description:RNAPII pausing/termination shortly after initiation is a hallmark of gene regulation. However, the molecular mechanisms involved are still to be uncovered. Here, we show that NELF interacts with Integrator complex subunits (INTScom) forming a stable complex with RNPII and Spt5. The interaction between NELF and INTScom subunits is RNA and DNA independent. Using both HIV-1 promoter and genome wide analyses, we demonstrate that Integrator subunits specifically control NELF-mediated RNAPII pause/release at coding genes. The strength of RNAPII pausing is determined by the nature of the NELF-associated complex. Interestingly, in addition to controlling RNAPII pause release INTS11 catalytic subunit of the INTScom is required for the synthesis of full length mRNA. Finally, INTScom-target genes are enriched in HIV-1 TAR/ NELF-binding element and in a 3’box sequence required for snRNA biogenesis. Revealing these unexpected functions of INTScom in regulating RNAPII pausing/release and completion of mRNA synthesis of NELF-target genes will contribute to our understanding of the gene expression cycle. Genome-wide expression in HeLa cells in the absence of Integrator 11, or NELF or mock (control) depleted by strand-specific RNASeq (Illumina)

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