title: Histone Methylation by the Kleefstra Syndrome Protein EHMT1 Mediates Homeostatic Synaptic Scaling.
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.
authors.affiliation: 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.
authors.forename: Marco
authors.initials: M
authors.lastname: Benevento
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6500 HB Nijmegen, the Netherlands.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Iacono
authors.affiliation: 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.
authors.forename: Martijn
authors.initials: M
authors.lastname: Selten
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Ba
authors.affiliation: 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.
authors.forename: Astrid
authors.initials: A
authors.lastname: Oudakker
authors.affiliation: 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.
authors.forename: Monica
authors.initials: M
authors.lastname: Frega
authors.affiliation: 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.
authors.forename: Jason
authors.initials: J
authors.lastname: Keller
authors.affiliation: 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.
authors.forename: Roberta
authors.initials: R
authors.lastname: Mancini
authors.affiliation: 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.
authors.forename: Elly
authors.initials: E
authors.lastname: Lewerissa
authors.affiliation: 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.
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud University, 6500 HB Nijmegen, the Netherlands.
authors.forename: Henk G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: 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.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.affiliation: 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.
authors.forename: Nael
authors.initials: N
authors.lastname: Nadif Kasri
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9 / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000378:metabolism / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000378:metabolism / Q000503:physiopathology; D006624:Hippocampus / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006657:Histones / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D008607:Intellectual Disability / Q000378:metabolism / Q000503:physiopathology; D008745:Methylation; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D013569:Synapses / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D006657:Histones; C513479:GLP protein, mouse; D011495:Histone-Lysine N-Methyltransferase