While DNA methylation and distinct RNA species have hogged the limelight in the ongoing tale of paternal epigenetic inheritance, a genetic mouse model now casts histone methylation as a leading player in this gripping transgenerational story.
A previous study led by Sarah Kimmins (McGill University, Montreal, Canada) found that reduced H3 lysine 4 dimethylation (H3K4me2) in sperm following the germline-specific overexpression of the human KDM1A H3K4 demethylase prompted developmental aberrations in offspring after crossing with a wild-type female. Interestingly, later generations of offspring that do not overexpress KDM1A also inherited the observed developmental aberrations. The authors established that H3K4me2 or DNA methylation did not mediate this inheritance, thereby suggesting a prominent role for another histone modification that can escape germline reprogramming to influence transgenerational phenotypes.
Now, a collaboration with Vanessa Dumeaux (Concordia University, Montreal, Canada) took advantage of the KDM1A genetic model of transgenerational epigenetic inheritance to explore the histone modification signatures involved.
The lights have dimmed, and the curtain is rising as Lismer, Siklenka, and colleagues take to the epigenetic stage to tell their transgenerational tale:
- Sperm-specific ChIP-sequencing in KDM1A-overexpressing mice revealed significant enrichment of histone H3 lysine 4 trimethylation (H3K4me3) at promoters outside of H3K4me3/H3K27me3 bivalent domains when compared to wild-type mice
- In contrast, KDM1A overexpression failed to influence H3K27me3 levels
- Analysis of sperm from descendants not overexpressing KDM1A revealed an H3K4me3 profile like that of sperm derived from KDM1A-overexpressing mice
- This finding suggested that H3K4me3-modified non-bivalent promoters escape epigenetic reprogramming, with affected genes include those associated with the observed transgenerational phenotypes
- Analysis of the paternal allele of pre-implantation embryos of descendants also highlighted regions of altered H3K4me3 enrichment that matched those observed in sperm
Overall, these dramatic new findings provide evidence that H3K4me3 avoids reprogramming during spermatogenesis and embryogenesis, thereby allowing transmission to later generations to influence gene expression profiles. This study firmly pushes this histone modification into the spotlight as a leading player in the transgenerational epigenetic inheritance of behavior in mice.
As the curtain comes down, we turn to the authors for their thoughts. “This study adds another piece to the puzzle as we try to determine the role of H3K4me3 in epigenetic inheritance. The next steps will be to identify how it escapes reprogramming in the embryo.”
While we wait with bated breath for the much anticipated “encores” of this research, read all the details on how histone methylation takes center stage in transgenerational epigenetic inheritance at Nucleic Acids Research, November 2020.