Cell-type specific DNA methylome signatures reveal epigenetic mechanisms for neuronal diversity and neurodevelopmental disorder

We report the application of an affinity purification approach (INTACT) to isolate tagged nuclei for GABAergic (GABA), Glutamatergic (Glu), and Purkinje neurons in mice. We performed whole-genome bisulfite sequencing (WGBS) to explore the cell type-specific DNA methylation signatures for the three neuronal types, together with matched transcriptomics. We found a substantial number of differentially methylated regions (DMRs) between cell types, characterized cell-type specific DMRs, and estimated the effects of DNA methylation on gene expression. Finally, we revealed that DNA methylation altered in a cell-type specific manner in a mouse model of Rett syndrome, a neurodevelopmental disorder caused by Mecp2 loss of function. The presented data emphasize the important role of DNA methylation-mediated epigenetic regulation in neuronal diversity and disease. WGBS and RNA-Seq for mouse GABAergic, Glutamatergic and Purkinje neurons, as well as for GABAergic and Glutamatergic neurons with Mecp2 KO. Only male mice were included in this project. For the nuclei isolated from one mouse, half of them were used for DNA extraction, and another half were used for RNA-Seq extraction. Therefore, each sample has DNA and matched RNA for WGBS and RNA-Seq, respectively.