Molecular Mechanisms of Transgenerational Inheritance of DNA Methylation in Mammals

Abstract

Accumulating evidence indicates that there is a form of inheritance that traditional genetics fails to explain. Epigenetic factors, like DNA methylation, can affect gene expression without altering DNA sequence and there is evidence of their inheritance in mammals, but the molecular mechanisms remain unknown. Transgenerational epigenetic inheritance refers to the transmission of an epigenetic mark to subsequent generations, in the absence of the original environmental stimulus that initially caused it. This literary review aims to present current knowledge of the potential molecular mechanisms of transgenerational inheritance of DNA methylation in mammals.

DNA methylation is a chemical modification of DNA, catalysed by DNA methyl transferases, which often has a silencing effect on gene expression. Methylation patterns are maintained through mitosis by UHRF1 which recognises hemimethylated sites and recruits DNA methyl transferases to copy the methylation patterns to the newly synthesised DNA.

Both direct and indirect mechanisms for DNA methylation transmission in meiosis have been proposed. The direct, replicative transmission utilises the same mechanism that occurs in mitosis. This mechanism is unlikely to transmit DNA methylation patterns across generations because of two genome-wide demethylation events that occur during gametogenesis and early embryonic development.

The indirect mechanisms rely on secondary signals, such as non-coding RNA, histone modifications and transcription factors, that mediate DNA methylation after global demethylation. Evidence of the interaction between de novo DNA methyl transferases and secondary signals suggests that the secondary signals could recruit and guide DNA methyl transferases to specific loci. This reconstructive mechanism is the more likely mechanism for the transgenerational inheritance of DNA methylation.

Further studies are needed to establish the precise mechanisms of transgenerational inheritance of DNA methylation in mammals. It is most likely that several factors contribute to the inheritance of DNA methylation, but current research fails to consider the interplay of different mechanisms.