# Chromatin-mediated alternative splicing in reward pathophysiology

> **NIH NIH DP1** · UNIVERSITY OF PENNSYLVANIA · 2021 · $483,000

## Abstract

PROJECT SUMMARY
 The epigenome refers to covalent modifications of nuclear histone proteins and their
associated DNA, which function to regulate gene expression. There is a wealth of data
implicating epigenetic remodeling in neurobiological function and behavior, especially in the
context of reward pathologies, such as addiction and depression. However, due to the
promiscuity of the factors involved, previous studies have failed to distinguish between the mere
presence and the functional relevance of a given chromatin modification at a specific gene.
This limits the elucidation of the precise molecular mechanisms by which neuroepigenetic
remodeling regulates transcription. To address this, we utilize a multidisciplinary approach that
involves (1) analysis of chromatin immunoprecipiation (ChIP)- and RNA-sequencing (seq)
datasets from brain reward regions following volitional reward behavior and (2) direct
manipulation of such modifications, using an innovative strategy of gene-targeted epigenetic
editing using engineered transcription factors (ETFs).
 The current proposal tests the hypothesis that histone posttranslational modifications
(HPTMs), specifically histone H3 lysine 36 methylation (H3K36me3), directly functions in
reward-mediated pre-mRNA alternative splicing. The rationale for this hypothesis includes
recently published data that both alternative splicing and H3K36me3 enrichment are highly
regulated by cocaine exposure, and our preliminary finding that there is a significant correlation
between genome-wide H3K36me3 enrichment and the splicing complexity of expressed
alternative isoforms. While chromatin-mediated alternative splicing is well established in cell-
culture systems, it has not yet been described as a mechanism in brain, despite the prevalence
of both widespread chromatin remodeling and alternative splicing in neurons. This proposal
outlines a novel strategy to demonstrate neuronal H3K36me3-mediated alternative splicing, and
the functional significance of this transcriptional mechanism to motivated behavior. In particular,
we will analyze neuronal changes in mouse brain reward regions following drug or natural
reward self-administration. This work will establish a strategy through which we can examine
additional mechanisms of chromatin-mediated alternative splicing in various brain regions,
expanding beyond the initial hypotheses of the current proposal.

## Key facts

- **NIH application ID:** 10188481
- **Project number:** 5DP1DA044250-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Elizabeth A Heller
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $483,000
- **Award type:** 5
- **Project period:** 2017-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10188481

## Citation

> US National Institutes of Health, RePORTER application 10188481, Chromatin-mediated alternative splicing in reward pathophysiology (5DP1DA044250-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10188481. Licensed CC0.

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