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Background  Programmed epigenetic modifications occurring at early postnatal brain developmental stages may have a long-lasting impact on brain function and complex behavior throughout life. Notably, it is now emerging that several genes that undergo perinatal changes in DNA methylation are associated with neuropsychiatric disorders. In this context, we envisaged that epigenetic modifications during the perinatal period may potentially drive essential changes in the genes regulating brain levels of critical neuromodulators such as  d -serine and  d -aspartate. Dysfunction of this fine regulation may contribute to the genesis of schizophrenia or other mental disorders, in which altered levels of  d -amino acids are found. We recently demonstrated that  Ddo , the  d -aspartate degradation gene, is actively demethylated to ultimately reduce  d -aspartate levels. However, the role of epigenetics as a mechanism driving the regulation of appropriate  d -ser levels during brain development has been poorly investigated to date.    Methods  We performed comprehensive ultradeep DNA methylation and hydroxymethylation profiling along with mRNA expression and HPLC-based  d -amino acids level analyses of genes controlling the mammalian brain levels of  d -serine and  d -aspartate. DNA methylation changes occurring in specific cerebellar cell types were also investigated. We conducted high coverage targeted bisulfite sequencing by next-generation sequencing and single-molecule bioinformatic analysis.    Results  We report consistent spatiotemporal modifications occurring at the  Dao  gene during neonatal development in a specific brain region (the cerebellum) and within specific cell types (astrocytes) for the first time. Dynamic demethylation at two specific CpG sites located just downstream of the transcription start site was sufficient to strongly activate the  Dao  gene, ultimately promoting the complete physiological degradation of cerebellar  d -serine a few days after mouse birth. High amount of 5′-hydroxymethylcytosine, exclusively detected at relevant CpG sites, strongly evoked the occurrence of an active demethylation process.    Conclusion  The present investigation demonstrates that robust and selective demethylation of two CpG sites is associated with postnatal activation of the  Dao  gene and consequent removal of  d -serine within the mouse cerebellum. A single-molecule methylation approach applied at the  Dao  locus promises to identify different cell-type compositions and functions in different brain areas and developmental stages.    Electronic supplementary material  The online version of this article (10.1186/s13148-019-0732-z) contains supplementary material, which is available to authorized users.

Selective demethylation of two CpG sites causes postnatal activation of the Dao gene and consequent removal of d-serine within the mouse cerebellum