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Cell Rep. 2019 Jan 29;26(5):1174-1188.e5. doi: 10.1016/j.celrep.2019.01.032.

Enhancer Histone Acetylation Modulates Transcriptional Bursting Dynamics of Neuronal Activity-Inducible Genes.

Author information

1
Department of Neurobiology, Duke University, Durham, NC 27710, USA.
2
Center for Nonlinear Studies (T-CNLS) and Theoretical Biology and Biophysics Group (T-6), Theoretical Division, Los Alamos National Laboratory, NM 87545, USA.
3
Program in Computational Biology and Bioinformatics, Duke University, Durham, NC 27710, USA; Center for Genomic and Computational Biology, Duke University, Durham, NC 27710, USA; Department of Biology, Duke University, Durham, NC 27710, USA.
4
Center for Genomic and Computational Biology, Duke University, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA.
5
Center for Genomic and Computational Biology, Duke University, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA; Department of Orthopaedic Surgery, Duke University, Durham, NC 27710, USA.
6
Center for Genomic and Computational Biology, Duke University, Durham, NC 27710, USA; Department of Biology, Duke University, Durham, NC 27710, USA; Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC 27606, USA. Electronic address: nebuchle@ncsu.edu.
7
Department of Neurobiology, Duke University, Durham, NC 27710, USA. Electronic address: west@neuro.duke.edu.

Abstract

Neuronal activity-inducible gene transcription correlates with rapid and transient increases in histone acetylation at promoters and enhancers of activity-regulated genes. Exactly how histone acetylation modulates transcription of these genes has remained unknown. We used single-cell in situ transcriptional analysis to show that Fos and Npas4 are transcribed in stochastic bursts in mouse neurons and that membrane depolarization increases mRNA expression by increasing burst frequency. We then expressed dCas9-p300 or dCas9-HDAC8 fusion proteins to mimic or block activity-induced histone acetylation locally at enhancers. Adding histone acetylation increased Fos transcription by prolonging burst duration and resulted in higher Fos protein levels and an elevation of resting membrane potential. Inhibiting histone acetylation reduced Fos transcription by reducing burst frequency and impaired experience-dependent Fos protein induction in the hippocampus in vivo. Thus, activity-inducible histone acetylation tunes the transcriptional dynamics of experience-regulated genes to affect selective changes in neuronal gene expression and cellular function.

KEYWORDS:

CRISPR; enhancer; epigenome editing; histone acetylation; neuronal activity-inducible transcription; transcriptional bursting

PMID:
30699347
PMCID:
PMC6376993
DOI:
10.1016/j.celrep.2019.01.032
[Indexed for MEDLINE]
Free PMC Article

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