DNA methylation confers a cerebellum specific identity in non-human primates

Selective gene expression in various brain regions is crucial for establishing and maintaining distinct subdivision identities. DNA methylation, as well-studied fundamental regulator of gene transcription, involves the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). It is believed to play essential roles in regulating brain identity by influencing gene expression patterns. However, the direct association of DNA methylation with brain identity, especially in primate brains, remains largely unexplored. In the current study involving 12 rhesus monkeys, we conducted a comprehensive analysis of the DNA methylation landscape and gene transcription patterns in four brain regions (cortex, cerebellum, striatum and hippocampus). Our investigation revealed unique patterns of 5mC, 5hmC, and gene expression in the cerebellum. Notably, differentially methylated regions (DMRs) in the monkey cerebellum were found to be enriched in metabolic pathways. Intriguingly, genes with clustered differentially hydroxylmethylated regions (DhMRs) were found to overlap with genes related to schizophrenia. Moreover, we discovered that 5mC located 1 kilobase upstream of ATG start codon is correlated with gene expression and associated with 5hmC regulation in various directions. These findings shed light on the coordinated regulation of cerebellum-specific 5mC and 5hmC, which contribute to cerebellum identity and associated diseases.