Methyl-CpG binding domain 2 (Mbd2) deficiency causes cognitive, social and emotional deficits and down-regulation of ortholog Autism risk genes

Methyl-CpG-binding domain 2 (Mbd2) binds methylated DNA and was shown to play an important role in cancer and immunity but its role in brain function is mostly unknown. Here we show that Mbd2-deficiency in mice results in deficits in cognitive, social and emotional functions. Chromatin immunoprecipitation (ChIP-seq) revealed that Mbd2 binds to regulatory DNA regions of neuronal genes in the hippocampus. Loss of mbd2 alters the expression of hundreds of genes with a robust down-regulation of neuronal gene pathways. Genes down-regulated by loss of mbd2 are highly enriched for ortholog Autism Spectrum Disorder (ASD) risk genes. Further, a genome-wide DNA methylation analysis found an altered DNA methylation pattern in regulatory DNA regions of neuronal specific genes in mbd2 deficient mice. Intra-hippocampal viral down-regulation of mbd2 recapitulate most of the behavioral phenotypes observed in knockout mice. Taken together, our data suggest that Mbd2 regulates hippocampal DNA methylation landscape to control neuronal gene expression and ASD-like phenotypic behaviors.