During the final stages of sperm formation, most histones are replaced by sperm-specific protamine proteins to enable DNA compaction in sperm nuclei. The function of the retained nucleosomes in transgenerational inheritance is largely unknown. Siklenka et al. reduced the dimethylation of histone H3 Lys 4 (H3K4me2) in mouse sperm by overexpressing the human Lys demethylase KDM1A (also known as LSD1) specifically in the male germ line. This led to H3K4me2 loss in many developmental genes. The offspring of heterozygous transgenic males showed severe developmental defects, which were transmitted paternally through three generations, even when KDM1A was not expressed in the offspring germ line. No changes in DNA methylation were observed at CpG islands, whereas RNA profiles were altered in the sperm of transgenic males and their offspring, suggesting an important role for sperm histone methylation in transgenerational inheritance.
References
Siklenka et al. Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science http://dx.doi.org/10.1126/science.aab2006 (2015)
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Baumann, K. Methylation in paternal inheritance. Nat Rev Mol Cell Biol 16, 641 (2015). https://doi.org/10.1038/nrm4081
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DOI: https://doi.org/10.1038/nrm4081