Proper chromatin programming during spermatogenesis is required for embryonic development

Epigenetic mechanisms including DNA methylation, non-coding RNAs and histone modifications control gene expression. Studies suggest that a father's lifetime experiences can be transmitted to his offspring to affect development and health. The mechanisms underlying such epigenetic inheritance are unknown. A potential route for paternal transmission is the unique chromatin composition of spermatozoa. Unlike somatic cells and oocytes, most nucleosomes in sperm are replaced with protamine nucleoproteins. The role of residual nucleosomes, residing at gene regulatory sequences, for epigenetic control of embryonic development is unknown. Here we generated a transgenic mouse model in which over-expression of the histone H3 lysine 4 (H3K4) demethylase LSD1/KDM1A during spermatogenesis alters H3K4 methylation in sperm. Strikingly, KDM1A over-expression in one generation causes severe embryonic defects in non-transgenic descendants spanning three subsequent generations. We show for the first time that correct histone methylation homeostasis during spermatogenesis is critical for offspring development and survival over multiple generations.