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Integrator mediates the biogenesis of enhancer RNAs

Nature volume 525, pages 399403 (17 September 2015) | Download Citation


Integrator is a multi-subunit complex stably associated with the carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII)1. Integrator is endowed with a core catalytic RNA endonuclease activity, which is required for the 3′-end processing of non-polyadenylated, RNAPII-dependent, uridylate-rich, small nuclear RNA genes1. Here we examine the requirement of Integrator in the biogenesis of transcripts derived from distal regulatory elements (enhancers) involved in tissue- and temporal-specific regulation of gene expression in metazoans2,3,4,5. Integrator is recruited to enhancers and super-enhancers in a stimulus-dependent manner. Functional depletion of Integrator subunits diminishes the signal-dependent induction of enhancer RNAs (eRNAs) and abrogates stimulus-induced enhancer–promoter chromatin looping. Global nuclear run-on and RNAPII profiling reveals a role for Integrator in 3′-end cleavage of eRNA primary transcripts leading to transcriptional termination. In the absence of Integrator, eRNAs remain bound to RNAPII and their primary transcripts accumulate. Notably, the induction of eRNAs and gene expression responsiveness requires the catalytic activity of Integrator complex. We propose a role for Integrator in biogenesis of eRNAs and enhancer function in metazoans.

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Gene Expression Omnibus

Data deposits

High-throughput data are deposited at the Gene Expression Omnibus (GEO) under accession number GSE68401.


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We would like to thank J. M. Marinis and M. A. Lazar for technical support for GRO-seq experiments. We thank D. Hu in A. Shilatifard’s laboratory for performing the SEC ChIP-seq experiments. We thank the Oncogenomics core facility at Sylvester Comprehensive Cancer Center for performing high-throughput sequencing. We also thank Shiekhattar laboratory members and P.-J. Hamard for support and discussions. This work was supported by funds from University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center and grants R01 GM078455 and R01 GM105754 (R.S.) from the National Institute of Health.

Author information

Author notes

    • Fan Lai
    •  & Alessandro Gardini

    These authors contributed equally to this work.


  1. University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Department of Human Genetics, Biomedical Research Building, Room 719, 1501 NW 10th Avenue, Miami, Florida 33136, USA

    • Fan Lai
    • , Alessandro Gardini
    • , Anda Zhang
    •  & Ramin Shiekhattar


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F.L. and A.G. are co-first authors. R.S., F.L. and A.G. conceived and designed the overall project. F.L., A.G. and A.Z. performed the experiments. R.S., F.L. and A.G. analysed the data and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ramin Shiekhattar.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    This table contains a list of 91 EGF stimulated enhancer RNA loci.

  2. 2.

    Supplementary Table 2

    This table contains all the PCR primer sequences and hairpin sequences.

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