The Integrator complex terminates promoter-proximal transcription at protein-coding genes

Abstract

Highlights:• The Integrator complex inhibits transcription elongation at ~15% of mRNA genes• Integrator targets promoter-proximally paused Pol II for termination• The RNA endonuclease of Integrator subunit 11 is critical for gene attenuation • Integrator-repressed genes are enriched in signaling and growth-responsive pathways SUMMARY 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 might dissociate from template DNA at these promoters and release a short, non-productive mRNA.Here, we report that paused Pol II can be actively destabilized by the Integrator complex. Specifically, Integrator utilizes its RNA endonuclease activity to cleave nascent RNA and drive termination of paused Pol II. These findings uncover a previously unappreciated mechanism of metazoan gene repression, akin to bacterial transcription attenuation, wherein promoter-proximal Pol II is prevented from entering productive elongation through factor-regulated termination.

A Two-Layered Targeting Mechanism Underlies Nuclear RNA Sorting by the Human Exosome

“…Our analysis of protein-coding genes argues that this phenomenon is not just restricted to loci producing cryptic transcripts. Moreover, it suggests that TSS-proximal termination events may extend well beyond previously reported examples (Elrod et al, 2019;Iasillo et al, 2017;Kamieniarz-Gdula et al, 2019;Ogami et al, 2017;Tatomer et al, 2020).…”

Integrator restrains paraspeckles assembly by promoting isoform switching of the lncRNA NEAT1

“…Integrator interacts with the CTD of RNA Pol II and processes newly transcribed RNA molecules, mainly nonpolyadenylated transcripts and UsnRNAs. Integrator has also been recently implicated in the modulation of gene expression via regulation of protein-coding gene transcription initiation and premature termination (7,27), in RNA Pol II pause release (31,32), and in the biogenesis of enhancer RNAs (6). Here, we provide functional evidence for an unexpected role of Integrator in the regulation of the isoform switching of the lncRNA NEAT1.…”

“…(H) Western blot analysis for p53, p21, and phospho-H2AX, confirming the efficacy of the treatments; GAPDH is a loading control. (7,27), in RNA Pol II pause release (31,32), and in the biogenesis of enhancer RNAs (6). Here, we provide functional evidence for an unexpected role of Integrator in the regulation of the isoform switching of the lncRNA NEAT1.…”

Molecular Basis of the Function of Transcriptional Enhancers

“…A recent study by Nathan D. Elrod et al showed that Integrator can actively destabilize paused Pol II at the mRNA of coding genes as well. Similarly, Integrator utilizes its RNA endonuclease activity to cleave nascent RNA and drive the termination of paused Pol II [115]. Taken together, these findings reveal a previously unappreciated mechanism of transcription suppression inherent to promoters and enhancers alike.…”