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

Chen, Liang-Fu; Lin, Yen Ting; Gallegos, David A.; Hazlett, Mariah F.; Gómez-Schiavon, Mariana; Yang, Marty G.; Kalmeta, Breanna; Zhou, Allen S.; Holtzman, Liad; Gersbach, Charles A.; Grandl, Jörg; Buchler, Nicolas E.; West, Anne E.

doi:10.1016/j.celrep.2019.01.032

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

Journal Article · Tue Jan 29 00:00:00 EST 2019 · Cell Reports

DOI:https://doi.org/10.1016/j.celrep.2019.01.032· OSTI ID:1494468

Chen, Liang-Fu ^[1];

^[2]; Gallegos, David A. ^[1]; Hazlett, Mariah F. ^[1]; Gómez-Schiavon, Mariana ^[3]; Yang, Marty G. ^[1]; Kalmeta, Breanna ^[1]; Zhou, Allen S. ^[1]; Holtzman, Liad ^[4]; Gersbach, Charles A. ^[5]; Grandl, Jörg ^[1]; Buchler, Nicolas E. ^[6]; West, Anne E. ^[1]

Duke Univ., Durham, NC (United States). Dept. of Neurobiology
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Duke Univ., Durham, NC (United States). Program in Computational Biology and Bioinformatics, Center for Genomic and Computational Biology, and Dept. of Biology
Duke Univ., Durham, NC (United States). Center for Genomic and Computational Biology, and Dept. of Biomedical Engineering
Duke Univ., Durham, NC (United States). Center for Genomic and Computational Biology, Dept. of Biomedical Engineering, and Dept. of Orthopaedic Surgery
Duke Univ., Durham, NC (United States). Center for Genomic and Computational Biology, and Dept. of Biology; North Carolina State Univ., Raleigh, NC (United States). Dept. of Molecular Biomedical Sciences

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. Here, 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.

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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE Laboratory Directed Research and Development (LDRD) Program; National Institutes of Health (NIH)

Grant/Contract Number:: 89233218CNA000001; R21/R33 DA041878

OSTI ID:: 1494468

Report Number(s):: LA-UR-18-29362

Journal Information:: Cell Reports, Vol. 26, Issue 5; ISSN 2211-1247

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 62 works

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