Post-natal supply of GLP/Ehmt1 reverses Histone H3K9 dimethylation in cortical neuron isolated from adult Ehmt1∆/+ mice brain

EHMT1 haploinsufficiency causes Kleefstra syndrome (KS), a complex disorder of developmental delay and intellectual disability. EHMT1 encodes a lysine methyltransferase GLP and regulates histone H3 lysine 9 dimethylation (H3K9me2). Ehmt1 heterozygous mutant (Ehmt1∆/+) mice show KS-like abnormal behavioral phenotypes. Here, we examined the reversibility of decreased H3K9me2 by postnatal supply of GLP in post-mitotic neuron of Ehmt1∆/+ mice brain. For this purpose, we generated the mice harboring inducible Ehmt1 cDNA with CamKII-creER (Ehmt1 iTG-neuron mice) in Ehmt1∆/+ background. These mice expressed exogenous Ehmt1 in post-mitotic neuron upon Tamoxifen treatment. Using these mice, we sorted out NeuN+ cells from cortical region and performed Histone H3 K9-dimethyation ChIP analysis. Here we showed that Ehmt1 haploinsufficiency induces global reduction of euchromatic H3K9me2 especially in the euchromatic region of brain and that postnatal supply of GLP can reverse the diminished H3K9me2 phenotype, even in a postmitotic situation. H3K9 dimethylation ChIP seq of NeuN+ cells isolated from wild type, Ehmt1∆/+, Ehmt1 Tg; CamKII-CreER and Ehmt1∆/+;Ehmt1 Tg; CamKII-CreER cortex after re-expression of GLP/Ehmt1 in pot-mitotic neuron