Paternal H3K4 methylation is required for minor zygotic gene activation and early mouse embryonic development.
Epigenetic modifications, such as DNA methylation and histone modifications, are dynamically altered predominantly in paternal pronuclei soon after fertilization. To identify which histone modifications are required for early embryonic development, we utilized histone K-M mutants, which prevent endogenous histone methylation at the mutated site. We prepared four single K-M mutants for histone H3.3, K4M, K9M, K27M, and K36M, and demonstrate that overexpression of H3.3 K4M in embryos before fertilization results in developmental arrest, whereas overexpression after fertilization does not affect the development. Furthermore, loss of H3K4 methylation decreases the level of minor zygotic gene activation (ZGA) predominantly in the paternal pronucleus, and we obtained similar results from knockdown of the H3K4 methyltransferase Mll3/4. We therefore conclude that H3K4 methylation, likely established by Mll3/4 at the early pronuclear stage, is essential for the onset of minor ZGA in the paternal pronucleus, which is necessary for subsequent preimplantation development in mice.
Laboratory of Pathology and Development, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku Tokyo, Japan Division of Molecular Pathobiology, Center for Zoonosis Control, Hokkaido University, Kita-ku Sapporo, Japan Research Fellow of Japan Society for the Promotion of Science, Chiyoda-ku Tokyo, Japan.
Keisuke
K
Aoshima
Laboratory of Pathology and Development, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku Tokyo, Japan.
Erina
E
Inoue
Division of Molecular Pathobiology, Center for Zoonosis Control, Hokkaido University, Kita-ku Sapporo, Japan.
Hirofumi
H
Sawa
Laboratory of Pathology and Development, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku Tokyo, Japan PRESTO, Japan Science and Technology Agency (JST), Kawaguchi-Honcho Saitama, Japan ytokada@iam.u-tokyo.ac.jp.
Yuki
Y
Okada
D000818:Animals; D047108:Embryonic Development / Q000235:genetics*; D044127:Epigenesis, Genetic; D005220:Fathers; D005260:Female; D005306:Fertilization / Q000235:genetics; D005307:Fertilization in Vitro; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D051379:Mice; D009154:Mutation; D011247:Pregnancy; D013094:Spermatozoa; D015533:Transcriptional Activation; D015053:Zygote / Q000502:physiology*
D006657:Histones; D008239:Lysine
K‐M mutant; Mll3/4; histone methylation; minor ZGA