Scruggs, B. S. et al. Bidirectional transcription arises from two distinct hubs of transcription factor binding and active chromatin. Mol. Cell 58, 1101–1112 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Adelman, K. & Lis, J. T. Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat. Rev. Genet. 13, 720–731 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rhee, H. S. & Pugh, B. F. Genome-wide structure and organization of eukaryotic pre-initiation complexes. Nature 483, 295–301 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Seila, A. C. et al. Divergent transcription from active promoters. Science 322, 1849–1851 (2008).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Preker, P. et al. RNA exosome depletion reveals transcription upstream of active human promoters. Science 322, 1851–1854 (2008).

Article  CAS  PubMed  Google Scholar 

Core, L. J., Waterfall, J. J. & Lis, J. T. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322, 1845–1848 (2008).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Core, L. J. et al. Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers. Nat. Genet. 46, 1311–1320 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kim, T. K. et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182–187 (2010).

Article  CAS  PubMed  PubMed Central  Google Scholar 

De Santa, F. et al. A large fraction of extragenic RNA pol II transcription sites overlap enhancers. PLoS Biol. 8, e1000384 (2010).

Article  PubMed  PubMed Central  Google Scholar 

Sigova, A. A. et al. Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells. Proc. Natl Acad. Sci. USA 110, 2876–2881 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Djebali, S. et al. Landscape of transcription in human cells. Nature 489, 101–108 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Almada, A. E., Wu, X., Kriz, A. J., Burge, C. B. & Sharp, P. A. Promoter directionality is controlled by U1 snRNP and polyadenylation signals. Nature 499, 360–363 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Chiu, A. C. et al. Transcriptional pause sites delineate stable nucleosome-associated premature polyadenylation suppressed by U1 snRNP. Mol. Cell 69, 648–663.e7 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Baillat, D. et al. Integrator, a multiprotein mediator of small nuclear RNA processing, associates with the C-terminal repeat of RNA polymerase II. Cell 123, 265–276 (2005).

Article  CAS  PubMed  Google Scholar 

Welsh, S. A. & Gardini, A. Genomic regulation of transcription and RNA processing by the multitasking Integrator complex. Nat. Rev. Mol. Cell Biol. 24, 204–220 (2023).

Article  CAS  PubMed  Google Scholar 

Offley, S. R. et al. A combinatorial approach to uncover an additional Integrator subunit. Cell Rep. 42, 112244 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Elrod, N. D. et al. The Integrator complex attenuates promoter-proximal transcription at protein-coding genes. Mol. Cell 76, 738–752.e7 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tatomer, D. C. & Wilusz, J. E. Attenuation of eukaryotic protein-coding gene expression via premature transcription termination. Cold Spring Harb. Symp. Quant. Biol. 84, 83–93 (2019).

Article  PubMed  Google Scholar 

Lykke-Andersen, S. et al. Integrator is a genome-wide attenuator of non-productive transcription. Mol. Cell 81, 514–529.e6 (2021).

Article  CAS  PubMed  Google Scholar 

Lai, F., Gardini, A., Zhang, A. & Shiekhattar, R. Integrator mediates the biogenesis of enhancer RNAs. Nature 525, 399–403 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rubtsova, M. P. et al. Integrator is a key component of human telomerase RNA biogenesis. Sci. Rep. 9, 1701 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Barra, J. et al. Integrator restrains paraspeckles assembly by promoting isoform switching of the lncRNA NEAT1. Sci. Adv. 6, eaaz9072 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cazalla, D., Xie, M. & Steitz, J. A. A primate herpesvirus uses the Integrator complex to generate viral microRNAs. Mol. Cell 43, 982–992 (2011).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zheng, H. et al. Identification of Integrator-PP2A complex (INTAC), an RNA polymerase II phosphatase. Science 370, eabb5872 (2020).

Article  CAS  PubMed  Google Scholar 

Fianu, I. et al. Structural basis of Integrator-mediated transcription regulation. Science 374, 883–887 (2021).

Article  CAS  PubMed  Google Scholar 

Stein, C. B. et al. Integrator endonuclease drives promoter-proximal termination at all RNA polymerase II-transcribed loci. Mol. Cell 82, 4232–4245.e11 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Huang, K. L. et al. Integrator recruits protein phosphatase 2A to prevent pause release and facilitate transcription termination. Mol. Cell 80, 345–358.e9 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Vervoort, S. J. et al. The PP2A-Integrator–CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer. Cell 184, 3143–3162.e32 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hu, S. et al. INTAC endonuclease and phosphatase modules differentially regulate transcription by RNA polymerase II. Mol. Cell 83, 1588–1604 (2023).

Article  CAS  PubMed  Google Scholar 

Gardini, A. et al. Integrator regulates transcriptional initiation and pause release following activation. Mol. Cell 56, 128–139 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yue, J. et al. Integrator orchestrates RAS/ERK1/2 signaling transcriptional programs. Genes Dev. 31, 1809–1820 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Beckedorff, F. et al. The human Integrator complex facilitates transcriptional elongation by endonucleolytic cleavage of nascent transcripts. Cell Rep. 32, 107917 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wang, H. et al. H3K4me3 regulates RNA polymerase II promoter-proximal pause-release. Nature 615, 339–348 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Stadelmayer, B. et al. Integrator complex regulates NELF-mediated RNA polymerase II pause/release and processivity at coding genes. Nat. Commun. 5, 5531 (2014).

Article  CAS  PubMed  Google Scholar 

Skaar, J. R. et al. The Integrator complex controls the termination of transcription at diverse classes of gene targets. Cell Res 25, 288–305 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Dasilva, L. F. et al. Integrator enforces the