Department of Neurobiology, Duke University, Durham, NC 27710, USA
Yen Ting Lin
Center for Nonlinear Studies (T-CNLS) and Theoretical Biology and Biophysics Group (T-6), Theoretical Division, Los Alamos National Laboratory, NM 87545, USA
David A. Gallegos
Department of Neurobiology, Duke University, Durham, NC 27710, USA
Mariah F. Hazlett
Department of Neurobiology, Duke University, Durham, NC 27710, USA
Mariana Gómez-Schiavon
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
Marty G. Yang
Department of Neurobiology, Duke University, Durham, NC 27710, USA
Breanna Kalmeta
Department of Neurobiology, Duke University, Durham, NC 27710, USA
Allen S. Zhou
Department of Neurobiology, Duke University, Durham, NC 27710, USA
Liad Holtzman
Center for Genomic and Computational Biology, Duke University, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA
Charles A. Gersbach
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
Jörg Grandl
Department of Neurobiology, Duke University, Durham, NC 27710, USA
Nicolas E. Buchler
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; Corresponding author
Anne E. West
Department of Neurobiology, Duke University, Durham, NC 27710, USA; Corresponding author
Summary: 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. : Using CRISPR-mediated epigenome editing, Chen et al. show that enhancer histone acetylation fine-tunes the activity-dependent transcription of Fos in neurons. Keywords: neuronal activity-inducible transcription, enhancer, histone acetylation, CRISPR, epigenome editing, transcriptional bursting
