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Neuron. 2016 Jul 20;91(2):341-55. doi: 10.1016/j.neuron.2016.06.003. Epub 2016 Jun 30.

Histone Methylation by the Kleefstra Syndrome Protein EHMT1 Mediates Homeostatic Synaptic Scaling.

Author information

1
Department of Cognitive Neuroscience, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, 6525 AJ Nijmegen, the Netherlands.
2
Department of Molecular Biology, Faculty of Science, Radboud University, 6500 HB Nijmegen, the Netherlands.
3
Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, 6525 AJ Nijmegen, the Netherlands.
4
Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Department of Molecular Developmental Biology, Faculty of Science, Radboud University, 6500 HB Nijmegen, the Netherlands.
5
Department of Cognitive Neuroscience, Radboudumc, 6500 HB Nijmegen, the Netherlands; Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, 6525 AJ Nijmegen, the Netherlands.
6
Department of Cognitive Neuroscience, Radboudumc, 6500 HB Nijmegen, the Netherlands; Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, 6525 AJ Nijmegen, the Netherlands. Electronic address: n.nadif@donders.ru.nl.

Abstract

Homeostatic plasticity, a form of synaptic plasticity, maintains the fine balance between overall excitation and inhibition in developing and mature neuronal networks. Although the synaptic mechanisms of homeostatic plasticity are well characterized, the associated transcriptional program remains poorly understood. We show that the Kleefstra-syndrome-associated protein EHMT1 plays a critical and cell-autonomous role in synaptic scaling by responding to attenuated neuronal firing or sensory drive. Chronic activity deprivation increased the amount of neuronal dimethylated H3 at lysine 9 (H3K9me2), the catalytic product of EHMT1 and an epigenetic marker for gene repression. Genetic knockdown and pharmacological blockade of EHMT1 or EHMT2 prevented the increase of H3K9me2 and synaptic scaling up. Furthermore, BDNF repression was preceded by EHMT1/2-mediated H3K9me2 deposition at the Bdnf promoter during synaptic scaling up, both in vitro and in vivo. Our findings suggest that H3K9me2-mediated changes in chromatin structure govern a repressive program that controls synaptic scaling.

PMID:
27373831
DOI:
10.1016/j.neuron.2016.06.003
[Indexed for MEDLINE]
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