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Nucleic Acids Res. 2018 Jun 1;46(10):4950-4965. doi: 10.1093/nar/gky196.

Increased H3K9 methylation and impaired expression of Protocadherins are associated with the cognitive dysfunctions of the Kleefstra syndrome.

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Radboud University, Department of Molecular Biology, Faculty of Science, 6500 HB Nijmegen, the Netherlands.
CELPHEDIA, PHENOMIN, Institut Clinique de la Souris, 1 rue Laurent Fries, 67404 Illkirch, France.
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.
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.
Institute of Molecular Genetics (IGMM), UMR5535, Centre National de Recherche Scientifique (CNRS), 1919 Route de Mende, 34293 Montpellier, France.
The University of Montpellier, 163 rue Auguste Broussonnet, 34090 Montpellier, France.


Kleefstra syndrome, a disease with intellectual disability, autism spectrum disorders and other developmental defects is caused in humans by haploinsufficiency of EHMT1. Although EHMT1 and its paralog EHMT2 were shown to be histone methyltransferases responsible for deposition of the di-methylated H3K9 (H3K9me2), the exact nature of epigenetic dysfunctions in Kleefstra syndrome remains unknown. Here, we found that the epigenome of Ehmt1+/- adult mouse brain displays a marked increase of H3K9me2/3 which correlates with impaired expression of protocadherins, master regulators of neuronal diversity. Increased H3K9me3 was present already at birth, indicating that aberrant methylation patterns are established during embryogenesis. Interestingly, we found that Ehmt2+/- mice do not present neither the marked increase of H3K9me2/3 nor the cognitive deficits found in Ehmt1+/- mice, indicating an evolutionary diversification of functions. Our finding of increased H3K9me3 in Ehmt1+/- mice is the first one supporting the notion that EHMT1 can quench the deposition of tri-methylation by other Histone methyltransferases, ultimately leading to impaired neurocognitive functioning. Our insights into the epigenetic pathophysiology of Kleefstra syndrome may offer guidance for future developments of therapeutic strategies for this disease.

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