# Enhancer RNA Regulation of Experience-dependent Neuroepigenetic Processes

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $382,307

## Abstract

Distal enhancer elements in DNA enable higher-order chromatin interactions that facilitate gene expression
programs and thus contribute to cellular phenotype and function. Enhancers regulate numerous aspects of cell
and tissue-specific gene expression patterns in the developing and adult brain, and have been highly
implicated in mental health and disease. In neuronal systems, enhancer elements are subject to widespread,
bidirectional transcription that yields non-coding enhancer RNA (eRNA). However, the precise function of
eRNAs is still unclear, with different models proposing unique regulatory functions. Emerging evidence
suggests that eRNAs function to modify epigenetic states at gene regulatory elements, which are critical for
long-term behavioral and neuronal plasticity. Specific Aim 1 of this proposal seeks to utilize whole-genome
sequencing approaches to define transcriptional and epigenetic signatures of neuronal activity at enhancers. In
addition to revealing new therapeutic candidates, this aim will employ novel targeted eRNA delivery strategies
based on CRISPR technology to allow manipulation of eRNAs at specific enhancers to determine their
function. Specific Aim 2 will examine interactions between eRNAs and epigenetic profiles at enhancers and
promoters of linked genes, which will establish the hierarchical relationships between molecular interactions at
enhancers. Specific Aim 3 will examine the contributions of eRNAs to neuronal function and memory formation
in the adult brain using hippocampus-dependent contextual fear conditioning, a robust assay of learning and
memory that requires activity-dependent gene transcription. This novel approach will demonstrate the
necessity of unique eRNAs at specific genes for neuronal activity and behavior, and also enable the first
investigation of whether modulation of eRNAs is sufficient to alter memory function. In addition to revealing the
exact nature and scope of eRNAs in neuronal gene regulation, this proposal will pave the way for future
experiments that will explore how manipulation of enhancers could be used to reprogram circuits that have
become maladaptive in mental illness and cognitive disease states.

## Key facts

- **NIH application ID:** 10138516
- **Project number:** 5R01MH114990-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** JEREMY J DAY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,307
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138516

## Citation

> US National Institutes of Health, RePORTER application 10138516, Enhancer RNA Regulation of Experience-dependent Neuroepigenetic Processes (5R01MH114990-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10138516. Licensed CC0.

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