Regenerative MedicineH3K9me3 Histone Mark Drives DNA Methylation Recovery After Germline Epigenome Editing
Japanese researchers developed a system to erase DNA methylation at the H19 imprinting control region specifically in mouse sperm, using a dead Cas9-TET1 fusion driven by a spermatogenesis-specific promoter. Methylation was completely eliminated in sperm, yet partially recovered after fertilization during pre-implantation development. Offspring of edited fathers showed Silver-Russell syndrome-like growth restriction, but only partially inherited the epimutation. Critically, when the histone mark H3K9me3 — deposited shortly after fertilization — was selectively removed from the H19-DMR in zygotes, subsequent de novo DNA methylation failed to recover. This identifies H3K9me3 as an epigenetic scaffold bridging sperm-borne methylation erasure to post-fertilization remethylation, with implications for understanding intergenerational inheritance and imprinting disorders.
