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

TitleEnhancer Histone Acetylation Modulates Transcriptional Bursting Dynamics of Neuronal Activity-Inducible Genes.
Publication TypeJournal Article
Year of Publication2019
AuthorsL-F Chen, YT Lin, DA Gallegos, MF Hazlett, M Gómez-Schiavon, MG Yang, B Kalmeta, AS Zhou, L Holtzman, CA Gersbach, J Grandl, NE Buchler, and AE West
JournalCell Reports
Volume26
Start Page1174
Issue5
Pagination1174 - 1188.e5
Date Published01/2019
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.

DOI10.1016/j.celrep.2019.01.032
Short TitleCell Reports