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Enhancer RNAs predict enhancer-gene regulatory links and are critical for enhancer function in neuronal systems

View ORCID ProfileNancy V. N. Carullo, View ORCID ProfileRobert A. Phillips III, Rhiana C. Simon, Salomon A. Roman Soto, Jenna E. Hinds, Aaron J. Salisbury, Jasmin S. Revanna, Kendra D. Bunner, View ORCID ProfileLara Ianov, Faraz A. Sultan, View ORCID ProfileKatherine E. Savell, View ORCID ProfileCharles A. Gersbach, View ORCID ProfileJeremy J. Day
doi: https://doi.org/10.1101/270967
Nancy V. N. Carullo
1Department of Neurobiology & Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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  • ORCID record for Nancy V. N. Carullo
Robert A. Phillips III
1Department of Neurobiology & Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Rhiana C. Simon
1Department of Neurobiology & Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Salomon A. Roman Soto
1Department of Neurobiology & Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Jenna E. Hinds
1Department of Neurobiology & Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Aaron J. Salisbury
1Department of Neurobiology & Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Jasmin S. Revanna
1Department of Neurobiology & Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Kendra D. Bunner
1Department of Neurobiology & Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Lara Ianov
2Civitan International Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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  • ORCID record for Lara Ianov
Faraz A. Sultan
1Department of Neurobiology & Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Katherine E. Savell
1Department of Neurobiology & Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Charles A. Gersbach
3Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA
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Jeremy J. Day
1Department of Neurobiology & Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA
2Civitan International Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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  • For correspondence: jjday@uab.edu
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Abstract

Genomic enhancer elements regulate gene expression programs important for neuronal fate and function and are implicated in brain disease states. Enhancers undergo bidirectional transcription to generate non-coding enhancer RNAs (eRNAs). However, eRNA function remains controversial. Here, we combined ATAC-Seq and RNA-Seq datasets from three distinct neuronal culture systems in two activity states, enabling genome-wide enhancer identification and prediction of putative enhancer-gene pairs based on correlation of transcriptional output. Notably, stimulus-dependent enhancer transcription preceded mRNA induction, and CRISPR- based activation of eRNA synthesis increased mRNA at paired genes, functionally validating enhancer-gene predictions. Focusing on enhancers surrounding the Fos gene, we report that targeted eRNA manipulation bidirectionally modulates Fos mRNA, and that Fos eRNAs directly interact with the histone acetyltransferase domain of the enhancer-linked transcriptional co-activator CBP. Together, these results highlight the unique role of eRNAs in neuronal gene regulation and demonstrate that eRNAs can be used to identify putative target genes.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • New ATAC-seq and RNA-seq datasets from three neuronal culture systems; analysis and genome-wide prediction of enhancer-gene pairs; text revision and reformatting.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted May 16, 2020.
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Enhancer RNAs predict enhancer-gene regulatory links and are critical for enhancer function in neuronal systems
Nancy V. N. Carullo, Robert A. Phillips III, Rhiana C. Simon, Salomon A. Roman Soto, Jenna E. Hinds, Aaron J. Salisbury, Jasmin S. Revanna, Kendra D. Bunner, Lara Ianov, Faraz A. Sultan, Katherine E. Savell, Charles A. Gersbach, Jeremy J. Day
bioRxiv 270967; doi: https://doi.org/10.1101/270967
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Enhancer RNAs predict enhancer-gene regulatory links and are critical for enhancer function in neuronal systems
Nancy V. N. Carullo, Robert A. Phillips III, Rhiana C. Simon, Salomon A. Roman Soto, Jenna E. Hinds, Aaron J. Salisbury, Jasmin S. Revanna, Kendra D. Bunner, Lara Ianov, Faraz A. Sultan, Katherine E. Savell, Charles A. Gersbach, Jeremy J. Day
bioRxiv 270967; doi: https://doi.org/10.1101/270967

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