@article{2d36f7d5e68e409f8678e41f6da6b682,
title = "The Integrator Complex Attenuates Promoter-Proximal Transcription at Protein-Coding Genes",
abstract = "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- to 60-nt-long nascent RNA for many minutes while awaiting signals for release into the gene body. However, 15%–20% 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, we present evidence that 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. Here, Elrod et al. demonstrate that the Integrator complex associates with paused RNA polymerase II at promoters and enhancers to terminate RNA synthesis. This attenuation mechanism potently represses expression of both stress- and growth-responsive genes in Drosophila and mammalian cells.",
keywords = "Integrator complex, enhancer RNA, histone methylation, polymerase pausing, transcription regulation, transcription termination",
author = "Elrod, {Nathan D.} and Telmo Henriques and Kai-Lieh Huang and Tatomer, {Deirdre C.} and Wilusz, {Jeremy E.} and Eric Wagner and Karen Adelman",
note = "Funding Information: We thank Todd Albrecht for generating Drosophila Integrator antibodies, Erik Andrulis for the Rrp40 antibody, William K. Russel and the UTMB Proteomics Core, and other members of the Adelman, Wilusz, and Wagner labs for helpful discussions. J.E.W. is a Rita Allen Foundation Scholar. This work was supported by NIH grants R35-GM119735 (to J.E.W.) and K99-GM131028 (to D.C.T.), Welch Foundation grant H-1889 (to E.J.W.), startup funds provided by Harvard Medical School (to K.A.), and R01 GM134539 (to K.A. and E.J.W.). Funding Information: We thank Todd Albrecht for generating Drosophila Integrator antibodies, Erik Andrulis for the Rrp40 antibody, William K. Russel and the UTMB Proteomics Core, and other members of the Adelman, Wilusz, and Wagner labs for helpful discussions. J.E.W. is a Rita Allen Foundation Scholar. This work was supported by NIH grants R35-GM119735 (to J.E.W.) and K99-GM131028 (to D.C.T.), Welch Foundation grant H-1889 (to E.J.W.), startup funds provided by Harvard Medical School (to K.A.), and R01 GM134539 (to K.A. and E.J.W.). T.H. N.D.E. K.-L.H. K.A. and E.J.W. designed and performed RNA-seq, ChIP, ChIP-seq, and PRO-seq experiments; T.H. N.D.E. and K.A. analyzed genomic datasets; and J.E.W. and D.C.T. performed northern blots and provided insights. K.A. and E.J.W. wrote the manuscript with input from all authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = dec,
day = "5",
doi = "10.1016/j.molcel.2019.10.034",
language = "English (US)",
volume = "76",
pages = "738--752.e7",
journal = "Molecular cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "5",
}