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

摘要

Neuronal activity-inducible gene transcription correlateswith rapid and transient increases in histoneacetylation at promoters and enhancers of activityregulatedgenes. Exactly how histone acetylationmodulates transcription of these genes has remainedunknown. We used single-cell in situ transcriptionalanalysis to show that Fos and Npas4 aretranscribed in stochastic bursts in mouse neuronsand that membrane depolarization increases mRNAexpression by increasing burst frequency. We thenexpressed dCas9-p300 or dCas9-HDAC8 fusionproteins to mimic or block activity-induced histoneacetylation locally at enhancers. Adding histoneacetylation increased Fos transcription by prolongingburst duration and resulted in higher Fos proteinlevels and an elevation of resting membrane potential.Inhibiting histone acetylation reduced Fostranscription by reducing burst frequency andimpaired experience-dependent Fos protein inductionin the hippocampus in vivo. Thus, activity-induciblehistone acetylation tunes the transcriptionaldynamics of experience-regulated genes to affectselective changes in neuronal gene expression andcellular function.