Journal article
H3.3 Barcoding of Nucleus Accumbens Transcriptional Activity Identifies Novel Molecular Cascades Associated with Cocaine Self-administration in Mice
The Journal of neuroscience, Vol.39(27), pp.5247-5254
07/03/2019
DOI: 10.1523/JNEUROSCI.0015-19.2019
PMCID: PMC6607753
PMID: 31043484
Abstract
Although numerous epigenetic modifications have been associated with addiction, little work has explored the turnover of histone variants. Uniquely, the H3.3 variant incorporates stably and preferentially into chromatin independently of DNA replication at active sites of transcription and transcription factor binding. Thus, genomic regions associated with H3.3-containing nucleosomes are particularly likely to be involved in plasticity, such as following repeated cocaine exposure. A recently developed mouse line expressing a neuron-specific hemagglutinin (HA)-tagged H3.3 protein was used to track transcriptionally active sites cumulatively across 19 d of cocaine self-administration. RNA-seq and H3.3-HA ChIP-seq analyses were performed on NAcc tissue collected following cocaine or food self-administration in male mice. RNA sequencing revealed five genes upregulated in cocaine relative to food self-administering mice:
Fosb
,
Npas4
,
Vgf
,
Nptx2
, and
Pmepa1
, which reflect known and novel cocaine plasticity-associated genes. Subsequent ChIP-seq analysis confirmed increased H3.3 aggregation at four of these five loci, thus validating H3.3 insertion as a marker of enhanced cocaine-induced transcription. Further motif recognition analysis of the ChIP-seq data showed that cocaine-associated differential H3.3 accumulation correlated with the presence of several transcription factor binding motifs, including RBPJ1, EGR1, and SOX4, suggesting that these are potentially important regulators of molecular cascades associated with cocaine-induced neuronal plasticity. Additional ontological analysis revealed differential H3.3 accumulation mainly near genes involved in neuronal differentiation and dendrite formation. These results establish the
H3.3-HA
transgenic mouse line as a compelling molecular barcoding tool to identify the cumulative effects of long-term environmental perturbations, such as exposure to drugs of abuse.
SIGNIFICANCE STATEMENT
Histone H3.3 is a core histone variant that is stably incorporated at active sites of transcription. We used a tagged version of H3.3 expressed exclusively in neurons to delineate active transcription sites following extended cocaine self-administration in mice. This approach revealed the cumulative list of genes expressed in response to cocaine taking over the course of several weeks. We combined this technique with RNA sequencing of tissue collected from the same animals 24 h after the last cocaine exposure. Comparing these datasets provided a full picture of genes that respond to chronic cocaine exposure in NAcc neurons. These studies revealed novel transcription factors that are likely involved in cocaine-induced plasticity and addiction-like behaviors.
Details
- Title: Subtitle
- H3.3 Barcoding of Nucleus Accumbens Transcriptional Activity Identifies Novel Molecular Cascades Associated with Cocaine Self-administration in Mice
- Creators
- Mathieu E Wimmer - Department of Psychology and Program in Neuroscience, Temple University, Philadelphia, Pennsylvania 19122Bruno Fant - Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, andSarah E Swinford-Jackson - Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, andAlexander Testino - Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, andDuncan Van Nest - Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, andTed Abel - Department of Molecular Physiology and Biophysics, Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa 52242R. Christopher Pierce - Department of Psychiatry, Center for Neurobiology and Behavior, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, and
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.39(27), pp.5247-5254
- Publisher
- Society for Neuroscience
- DOI
- 10.1523/JNEUROSCI.0015-19.2019
- PMID
- 31043484
- PMCID
- PMC6607753
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Language
- English
- Date published
- 07/03/2019
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
- Record Identifier
- 9984070130502771
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