While CpG methylation has received the seminal fame of transgenerational epigenetic inheritance, it seems that other players in the epigenome are just as capable. Sperm miRNAs have taken the solo spotlight in highlighting the mechanisms and distinction between transgenerational inheritance and intergenerational effect, but now histone methylation steps up to the plate leading us to wonder what other surprises exist upstream?
During sperm formation, most histones are removed and replaced with protoamines. However, some do remain and reason goes to suggest that they and their mods serve important developmental functions. Histone H3 lysine 4 (H3K4) methylation is transcriptionally activating and is demethylated by KDM1A (aka LSD1).
In this research, a team from McGill University in Canada used a transgenic mouse model to examine what happens when human KDM1A is overexpressed under the control of a germ-line specific promoter. By breeding these mice with wild-type females, they were able to create brothers that were either transgenic or not transgenic for human KDM1A and thus investigate what happens when an altered sperm H3K4 methlyome is transmitted to offspring.
Here’s what they found:
- One generation of germ-line overexpression resulted in an increased chance of abnormal skeletal development and reduced survival of offspring.
- Moving past intergenerational effect, the team found defects in the F3 generation in non-transgenic offspring, thus demonstrating transgenerational epigenetic inheritance.
- ChIP-seq showed that the overexpression of KDM1A resulted in a loss of H3K4me2 in over 2300 genes, many of which were related to development.
- Interestingly, reduced representation bisulfite sequencing and Sequenom MassARRAY methylation analysis showed no changes to DNA methylation in the CpG islands of sperm.
- However, microarrays showed that RNA content was changed in F1 sperm and F2 offspring at the two-cell stage.
Ultimately, this study provides some critical evidence for the role of sperm histone methylation in generating RNA content that is critical for transgenerational epigenetic inheritance. While a bit different than your average environmental exposure, the altered expression of the demethylase still hints that prospective fathers should start thinking about protecting their sperm epigenome.
Take a deeper look into the altered transmission of H3K4me2 in Science, November 2015