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

TitleEnhancer RNAs predict enhancer-gene regulatory links and are critical for enhancer function in neuronal systems.
Publication TypeJournal Article
Year of Publication2020
AuthorsNVN Carullo, RA Phillips Iii, RC Simon, SAR Soto, JE Hinds, AJ Salisbury, JS Revanna, KD Bunner, L Ianov, FA Sultan, KE Savell, CA Gersbach, and JJ Day
JournalNucleic Acids Research
Volume48
Start Page9550
Issue17
Pagination9550 - 9570
Date Published09/2020
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.

DOI10.1093/nar/gkaa671
Short TitleNucleic Acids Research