Journal
NEURON
Volume 74, Issue 1, Pages 122-135Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2012.02.021
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Funding
- Medical Research Council Toxicology Unit
- Samantha Dickson Brain Cancer Trust
- Wellcome Trust
- MRC [MC_U132670601] Funding Source: UKRI
- Medical Research Council [MC_U132670601] Funding Source: researchfish
- The Brain Tumour Charity [8/47] Funding Source: researchfish
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Activity-dependent modifications of chromatin are believed to contribute to dramatic changes in neuronal circuitry. The mechanisms underlying these modifications are not fully understood. The histone variant H3.3 is incorporated in a replication-independent manner into different regions of the genome, including gene regulatory elements. It is presently unknown whether H3.3 deposition is involved in neuronal activity-dependent events. Here, we analyze the role of the histone chaperone DAXX in the regulation of H3.3 incorporation at activity-dependent gene loci. DAXX is found to be associated with regulatory regions of selected activity-regulated genes, where it promotes H3.3 loading upon membrane depolarization. DAXX loss not only affects H3.3 deposition but also impairs transcriptional induction of these genes. Calcineurin-mediated dephosphorylation of DAXX is a key molecular switch controlling its function upon neuronal activation. Overall, these findings implicate the H3.3 chaperone DAXX in the regulation of activity-dependent events, thus revealing a new mechanism underlying epigenetic modifications in neurons.
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