Background DNA methylations at non-CpG sites (mCpHs) yield weak enrichment signals and co-localize with methylated CpGs (mCpGs). Accordingly, they are thought to represent byproducts of hyperactive methyltransferases. However, recent studies revealed that mCpHs are highly cell type-specific and associated with cellular functions in mammal, although their distributional and functional dependency to mCpGs remains to be elucidated.
Results Through computational analysis of a large publicly available DNA methylation dataset from human and mouse cells, we revealed that mCpHs tend to co-localize with mCpGs in pluripotent stem cells but not in brain cells. A systematic investigation using an empirical hidden Markov model confirmed that there are genomic regions where CpGs and CpHs are differentially methylated in the brain cells (~25%). Remarkably, the regions were frequently located in putative enhancers, and mCpHs within the enhancers were greatly increased as brain aged. We detected 1669 hyper-mCpH enhancers functionally enriched to immune system development, aberration of which can lead to neuro-inflammation and neuro-degeneration.
Conclusions In mammalian brain cells, there are genomic regions where CpH alone is methylated (or de-methylated). The mCpHs are accumulated in enhancers as brain aged, potentially associated to neuro-inflammation and degeneration. Altogether, this study provides insight into the roles of non-CpG methylation as an epigenetic code in the genomes of mammalian brain cells.