Derepression of inflammation-related genes link to microglia activation and neural maturation defect in a mouse model of Kleefstra Syndrome

Kleefstra syndrome (KS, also known as 9q.34.3 deletion syndrome) is a rare genetic disorder characterized by a developmental delay, abnormal behaviors and autism-like features. This syndrome is caused by haplo-insufficiency of the euchromatin histone methyltransferase 1 gene (EHMT1/GLP/KDM1D). This gene product, GLP is a methyltransferase responsible for mono- and di-methylation of lysine 9 on histone H3 N-terminal tail, which modulates epigenetic information. Ehmt1 heterozygous mutant (Ehmt1?/+) mice show KS-like abnormal behavioral phenotypes and utilized as KS model mice. Here, we isolated nuclei from adult Ehmt1?/+ mice cortex and analysed gene expression precisely by single nucleus RNA-seq analysis. It showed that many genes were up or down regulated in different cell types of Ehmt1?/+ mice brain. Among them, inflammation associating genes are up-regulated in Ehmt1?/+ mice neuronal cells. And this up-regulation was reversed by postnatal supply of GLP in post-mitotic neuron of Ehmt1?/+ mice brain. Overall design: Single nuclear RNAseq of Ehmt1 heterozygous KO mice cortex