NonCpG

Non-CpG methylation refers to DNA methylation that occurs at cytosines not followed by a guanine, i.e., in CpA, CpC, and CpT contexts (often described as CpH methylation). It is a component of the epigenetic landscape that complements the more common CpG methylation found throughout the genome.

Distribution and development are notable features. In mammals, non-CpG methylation is relatively rare in most somatic tissues but accumulates in embryonic stem cells and mature neurons. It increases during development in these lineages and tends to be low outside the brain and in many differentiated cell types. The pattern is tissue- and development-specific, making it a distinctive marker in certain cell types.

Mechanistically, non-CpG methylation is primarily established by de novo DNA methyltransferases, especially DNMT3A and DNMT3B. DNMT1, the enzyme responsible for maintenance of CpG methylation, plays a smaller or different role in non-CpG contexts. The turnover and precise maintenance of non-CpG methylation differ from CpG methylation and can depend on chromatin state and developmental timing.

Functionally, the role of non-CpG methylation is still being investigated. It is associated with gene regulation and chromatin states in neurons and stem cells and may contribute to neuronal maturation and plasticity. While correlations with transcriptional programs and regulatory elements have been reported, established causal relationships remain an active area of research.

Detection and analysis are typically performed using bisulfite sequencing, with data analyzed to distinguish methylation in CpH contexts from CpG methylation, enabling genome-wide mapping in relevant cell types.