Epigenetic Inheritance of DNA Methylation Patterns

Proper inheritance of DNA methylation patterns during cell division is critical for preserving cellular identity and preventing malignant cellular transformation. In humans, DNA methylation patterns are established during development and then maintained through multiple somatic cell divisions by co-operative activity of the de novo and maintenance DNA methyltransferases - DNMT3A/3B and DNMT1, respectively. A key question that remained unresolved is how the de novo DNMT3A/3B enzymes assist in faithful inheritance of methylation patterns in somatic cells while guarding against aberrant de novo DNA methylation. This study revealed a novel self-regulatory inheritance mechanism where DNMT3A/3B remain bound to nucleosomes containing methylated DNA, which stabilizes these proteins and enables faithful propagation of DNA methylation within the methylated domains through cooperative activity of DNMT3A/3B and DNMT1 enzymes. Such a mechanism not only ensures faithful somatic propagation of methylated states but also prevents aberrant de novo methylation by causing degradation of free DNMT3A/3B enzymes.