Figure 6. Model for intergenerational epigenetic inheritance following deletion of Kdm6a in the male germ line.

Kdm6a excision occurs in early spermatogenic precursors, resulting in genome-wide changes in H3K27me3 distribution. Altered H3K27me3 distribution biases nearby regions toward gain of DNA methylation. Both H3K27me3 and DNA methylation changes are retained in mature sperm. At fertilization, H3K27me3 and most DNA methylation changes are reset, but some DNA methylation gains persist. DNA methylation gains influence expression of nearby genes during development in genetically wild type F1 offspring. Effects on phenotype occur when downstream gene regulatory circuits are subjected to environmental or aging-associated stress.