Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring

ChIP-Sequencing for H3K4me3 was performed on the sperm of individual mice fed a folate sufficient or folate deficient diet, and on a wildtype or KDM1A overexpressing transgenic background. Ultra-Low-Input ChIP-Sequencing was performed on 8-cell embryos from male wildtype mice fed a folate sufficient or folate deficient diet. We identified regions of the sperm epigenome that were sensitive to a folate deficient diet and found that multiple epigenetic stressors could cumulatively alter H3K4me3 in sperm. Additionally, we found that alterations in H3K4me3 levels in the sperm of folate deficient males were retained in the pre-implantation embryo. Finally, low-input RNA-Seq on 8-cell embryos from folate sufficient or folate deficient males on a wildtype or KDM1A transgenic background allowed us identify transcripts with deregulated gene expression in the pre-implantation embryo. Regulating promoters with aberrant transcription in the 8-cell embryos overlapped promoters with altered H3K4me3 in sperm. Examination of H3K4me3 in the sperm of wildtype or KDM1A overexpressing transgenic mice fed a folate deficient or folate sufficient diet, examination of H3K4me3 in 8-cell embryos from wildtype males on a folate sufficient or folate deficient diet, and examination of gene expression in 8-cell embryos from folate sufficient or folate deficient males on a wildtype or KDM1A transgenic background.