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

Neuronal activity-inducible gene transcription correlates with rapid and transient increases in histone acetylation at promoters and enhancers of activity-regulated genes. However whether histone acetylation contributes to transcription of these genes has remained unknown. We used single-cell RNA expression data to show that Fos and Npas4 are transcribed in probabilistic 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, resulting in higher Fos protein levels and elevation of resting membrane potential. Inhibiting histone acetylation reduced Fos transcription by reducing burst frequency, and this impaired experience-dependent Fos protein induction in the hippocampus in vivo. Thus activity-inducible histone acetylation tunes the transcriptional dynamics of activity-regulated genes to impact experience-dependent changes in neuronal gene expression and cellular function.