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

Author:

Carullo Nancy V N1,Phillips III Robert A1,Simon Rhiana C1,Soto Salomon A Roman1,Hinds Jenna E1,Salisbury Aaron J1,Revanna Jasmin S1,Bunner Kendra D1,Ianov Lara2,Sultan Faraz A1,Savell Katherine E1,Gersbach Charles A3,Day Jeremy J12ORCID

Affiliation:

1. Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA

2. Civitan International Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA

3. Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA

Abstract

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 Assay for Transposase-Accessible Chromatin using Sequencing (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 CREB-binding protein (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.

Funder

NIH

UAB

Allen Distinguished Investigator Award

Paul G. Allen Frontiers Group

CIRC Emerging Scholar Award

Publisher

Oxford University Press (OUP)

Subject

Genetics

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