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Enhancers Predominantly Regulate Gene Expression in vivo Via Transcription Initiation

49 Pages Posted: 3 Jan 2020 Sneak Peek Status: Under Review

See all articles by Martin Stephen Charles Larke

Martin Stephen Charles Larke

University of Oxford - MRC Molecular Haematology Unit

Takayuki Nojima

University of Oxford - Sir William Dunn School of Pathology

Jelena Telenius

University of Oxford - MRC Molecular Haematology Unit

Jacqueline A. Sharpe

University of Oxford - MRC Molecular Haematology Unit

Jacqueline A. Sloane-Stanley

University of Oxford - MRC Molecular Haematology Unit

Sue Butler

University of Oxford - MRC Molecular Haematology Unit

Robert A. Beagrie

University of Oxford - MRC Molecular Haematology Unit

Damien J. Downes

University of Oxford - MRC Molecular Haematology Unit

Ron Schwessinger

University of Oxford - MRC Molecular Haematology Unit

A. Marieke Oudelaar

University of Oxford - MRC Molecular Haematology Unit

Julia Truch

University of Oxford - MRC Molecular Haematology Unit

Bryony Crompton

University of Oxford - MRC Molecular Haematology Unit

M. A. Bender

University of Oxford - Sir William Dunn School of Pathology

Nicholas J. Proudfoot

University of Oxford - Sir William Dunn School of Pathology

Douglas R. Higgs

University of Oxford - MRC Molecular Haematology Unit

Jim R. Hughes

University of Oxford - MRC Molecular Haematology Unit

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Abstract

Gene transcription occurs via a cycle of linked events including initiation, promoter proximal pausing and elongation of RNA polymerase II (Pol II). A key question is how do transcriptional enhancers influence these events to control gene expression? Here we have used a new approach to quantify transcriptional initiation and pausing in vivo, while simultaneously identifying transcription start sites (TSSs) and pause-sites (TPSs) from single RNA molecules. When analyzed in parallel with nascent RNA-seq, these data show that differential gene expression is achieved predominantly via changes in transcription initiation rather than Pol II pausing. Using genetically engineered mouse models deleted for specific enhancers we show that these elements control gene expression via Pol II recruitment and/or initiation rather than via promoter proximal pause release. Together, our data show that enhancers, in general, control gene expression predominantly by Pol II recruitment and initiation rather than via pausing.

Keywords: Pol II, transcription initiation, pausing, transcription, enhancer, Gene expression, nascent RNA, TSS, Premature termination, pause release, Pol II pausing, promoter proximal

Suggested Citation

Larke, Martin Stephen Charles and Nojima, Takayuki and Telenius, Jelena and Sharpe, Jacqueline A. and Sloane-Stanley, Jacqueline A. and Butler, Sue and Beagrie, Robert A. and Downes, Damien J. and Schwessinger, Ron and Oudelaar, A. Marieke and Truch, Julia and Crompton, Bryony and Bender, M. A. and Proudfoot, Nicholas J. and Higgs, Douglas R. and Hughes, Jim R., Enhancers Predominantly Regulate Gene Expression in vivo Via Transcription Initiation. CELL-D-19-03420. Available at SSRN: https://ssrn.com/abstract=3508885 or http://dx.doi.org/10.2139/ssrn.3508885
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Martin Stephen Charles Larke (Contact Author)

University of Oxford - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

Takayuki Nojima

University of Oxford - Sir William Dunn School of Pathology

South Parks Road
Oxford, OX1 3RE
United Kingdom

Jelena Telenius

University of Oxford - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

Jacqueline A. Sharpe

University of Oxford - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

Jacqueline A. Sloane-Stanley

University of Oxford - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

Sue Butler

University of Oxford - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

Robert A. Beagrie

University of Oxford - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

Damien J. Downes

University of Oxford - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

Ron Schwessinger

University of Oxford - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

A. Marieke Oudelaar

University of Oxford - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

Julia Truch

University of Oxford - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

Bryony Crompton

University of Oxford - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

M. A. Bender

University of Oxford - Sir William Dunn School of Pathology

South Parks Road
Oxford, OX1 3RE
United Kingdom

Nicholas J. Proudfoot

University of Oxford - Sir William Dunn School of Pathology

South Parks Road
Oxford, OX1 3RE
United Kingdom

Douglas R. Higgs

University of Oxford - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

Jim R. Hughes

University of Oxford - MRC Molecular Haematology Unit

Oxford, Oxfordshire, England
United Kingdom

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