Dataset Information

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

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.

SUBMITTER: Chen LF

PROVIDER: S-EPMC6376993 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Chen Liang-Fu LF Lin Yen Ting YT Gallegos David A DA Hazlett Mariah F MF Gómez-Schiavon Mariana M Yang Marty G MG Kalmeta Breanna B Zhou Allen S AS Holtzman Liad L Gersbach Charles A CA Grandl Jörg J Buchler Nicolas E NE West Anne E AE

Cell reports 20190101 5

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 exp ...[more]

PMID: 30699347

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Project description:The question of how the structure of a neuronal network affects its functionality has gained a lot of attention in neuroscience. However, the vast majority of the studies on structure-dynamics relationships consider few types of network structures and assess limited numbers of structural measures. In this in silico study, we employ a wide diversity of network topologies and search among many possibilities the aspects of structure that have the greatest effect on the network excitability. The network activity is simulated using two point-neuron models, where the neurons are activated by noisy fluctuation of the membrane potential and their connections are described by chemical synapse models, and statistics on the number and quality of the emergent network bursts are collected for each network type. We apply a prediction framework to the obtained data in order to find out the most relevant aspects of network structure. In this framework, predictors that use different sets of graph-theoretic measures are trained to estimate the activity properties, such as burst count or burst length, of the networks. The performances of these predictors are compared with each other. We show that the best performance in prediction of activity properties for networks with sharp in-degree distribution is obtained when the prediction is based on clustering coefficient. By contrast, for networks with broad in-degree distribution, the maximum eigenvalue of the connectivity graph gives the most accurate prediction. The results shown for small ([Formula: see text]) networks hold with few exceptions when different neuron models, different choices of neuron population and different average degrees are applied. We confirm our conclusions using larger ([Formula: see text]) networks as well. Our findings reveal the relevance of different aspects of network structure from the viewpoint of network excitability, and our integrative method could serve as a general framework for structure-dynamics studies in biosciences.

Dataset Information

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

Publications

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

Similar Datasets

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