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The non-coding snRNA 7SK controls transcriptional termination, poising, and bidirectionality in embryonic stem cells

Gonçalo Castelo-Branco15, Paulo P Amaral1, Pär G Engström26, Samuel C Robson1, Sueli C Marques5, Paul Bertone234 and Tony Kouzarides1*

Author Affiliations

1 The Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK

2 European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK

3 Genome Biology and Developmental Biology Units, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany

4 Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK

5 Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet,SE-17177 Stockholm, Sweden

6 Present address: Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Box 1031, SE-17121 Solna, Sweden

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Genome Biology 2013, 14:R98  doi:10.1186/gb-2013-14-9-r98

Published: 17 September 2013

Abstract

Background

Pluripotency is characterized by a unique transcriptional state, in which lineage-specification genes are poised for transcription upon exposure to appropriate stimuli, via a bivalency mechanism involving the simultaneous presence of activating and repressive methylation marks at promoter-associated histones. Recent evidence suggests that other mechanisms, such as RNA polymerase II pausing, might be operational in this process, but their regulation remains poorly understood.

Results

Here we identify the non-coding snRNA 7SK as a multifaceted regulator of transcription in embryonic stem cells. We find that 7SK represses a specific cohort of transcriptionally poised genes with bivalent or activating chromatin marks in these cells, suggesting a novel poising mechanism independent of Polycomb activity. Genome-wide analysis shows that 7SK also prevents transcription downstream of polyadenylation sites at several active genes, indicating that 7SK is required for normal transcriptional termination or control of 3′-UTR length. In addition, 7SK suppresses divergent upstream antisense transcription at more than 2,600 loci, including many that encode divergent long non-coding RNAs, a finding that implicates the 7SK snRNA in the control of transcriptional bidirectionality.

Conclusions

Our study indicates that a single non-coding RNA, the snRNA 7SK, is a gatekeeper of transcriptional termination and bidirectional transcription in embryonic stem cells and mediates transcriptional poising through a mechanism independent of chromatin bivalency.