The developing mammalian brain is particularly sensitive to epigenetic alterations, as observed by the fact that mutations in epigenetic effectors can result in human neurodevelopmental disorders.71,72
DNA methylation is highly dynamic in mammalian postnatal neurons and these cells express DNA methyltransferases (DNMT) at high levels.73
Importantly, deficiency in both DNMT1 and DNMT3A in forebrain excitatory neurons showed deficits in learning and memory,74
similar to deficits in fear memory observed with DNMT1 chemical inhibition.75
Likewise, DNMT3A regulates emotional behavior and spine plasticity76
and ensures the expression of key neurogenic genes by targeting non-promoter DNA methylation around active genes.77
In mammals, DNA methylation at CpG sites has traditionally been considered a repressive mark in the genome, as high DNA methylation levels in intergenic sequences and repetitive elements prevents spurious transcription while lack of DNA methylation in promoters and CpG islands promotes gene transcription.78,79
Surprisingly, recent genome-wide DNA methylation studies have shown that high CpG methylation is common in gene bodies (genomic loci spanning exons and introns) where it positively correlates with transcription.47,80
Furthermore, gene bodies contained in partially methylated domains (PMDs, continuous domains of <70% methylated CpGs) in human fibroblasts showed decreased expression compared to those contained in highly methylated domains.49
We have recently demonstrated that human neurons contain differential PMDs and that neuronal-specific large-scale methylation domains contain a functional subset of neuronally expressed genes that are highly enriched for autism candidate genes (Schroeder et al. in revision). Collectively, these studies suggest that neurons may require high levels of DNA methylation particularly around gene bodies for genes involved in calcium signaling, synaptic transmission and neuronal differentiation.
In addition to neuronal DNA methylation, the DNA methyl binding protein MeCP2 is highly expressed in mature neurons in the brain. MeCP2 is an essential “reader” of DNA methylation marks in brain and has diverse roles in transcriptional modulation,81,82
chromatin structural organization,83,84
and DNA repair.86
Mutations in MECP2
cause the autism spectrum disorder Rett syndrome,87
duplication of MECP2
causes intellectual disability with autism,88,89
and significantly lower MeCP2 levels are observed in 79% of autism postmortem brain samples, correlating with increased MECP2
These combined studies suggest that both DNA methylation and MeCP2 are part of a pathway critical for neuronal maturation in human development.
Interestingly, Rett syndrome brain and embryonic stem cell derived neural progenitor cells show increased levels of LINE-1
retrotransposition limited to neuronal tissues.91
These results suggest that neurons may be somewhat unique among human cell types in their controlled use of increased retrotransposon for genetic repeat diversity, and therefore may be more susceptible to changes in the genomic sink size. These results further implicate the role of DNA methylation and MeCP2 in the controlled regulation of LINE-1
retrotransposition and suggest that reduced DNA methylation and MeCP2 levels observed in autism90
may be contributing to genomic alterations of individual neurons in brain.