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Nature. 2016 Sep 22;537(7621):548-552. doi: 10.1038/nature19360. Epub 2016 Sep 14.

Broad histone H3K4me3 domains in mouse oocytes modulate maternal-to-zygotic transition.

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Department of Microbiology, Oslo University Hospital, Rikshospitalet, NO-0027 Oslo, Norway.
Ludwig Institute for Cancer Research, La Jolla, California 92093, USA.
Department of Gynecology, Section for Reproductive Medicine, Oslo University Hospital, Rikshospitalet, NO-0027, Oslo, Norway.
The Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, DK-2200 Copenhagen, Denmark.
Norwegian Transgenic Centre, Institute of Basic Medical Sciences, University of Oslo, NO-0317 Oslo, Norway.
Department of Tumor Biology and Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, NO-0424 Oslo, Norway.
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway.
Department of Nutrition, Faculty of Medicine, Institute of Basic Medical Sciences, University of Oslo, NO-0027 Oslo, Norway.
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, California 92093, USA.
UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, NO-0317 Oslo, Norway.


Maternal-to-zygotic transition (MZT) is essential for the formation of a new individual, but is still poorly understood despite recent progress in analysis of gene expression and DNA methylation in early embryogenesis. Dynamic histone modifications may have important roles in MZT, but direct measurements of chromatin states have been hindered by technical difficulties in profiling histone modifications from small quantities of cells. Recent improvements allow for 500 cell-equivalents of chromatin per reaction, but require 10,000 cells for initial steps or require a highly specialized microfluidics device that is not readily available. We developed a micro-scale chromatin immunoprecipitation and sequencing (μChIP-seq) method, which we used to profile genome-wide histone H3 lysine methylation (H3K4me3) and acetylation (H3K27ac) in mouse immature and metaphase II oocytes and in 2-cell and 8-cell embryos. Notably, we show that ~22% of the oocyte genome is associated with broad H3K4me3 domains that are anti-correlated with DNA methylation. The H3K4me3 signal becomes confined to transcriptional-start-site regions in 2-cell embryos, concomitant with the onset of major zygotic genome activation. Active removal of broad H3K4me3 domains by the lysine demethylases KDM5A and KDM5B is required for normal zygotic genome activation and is essential for early embryo development. Our results provide insight into the onset of the developmental program in mouse embryos and demonstrate a role for broad H3K4me3 domains in MZT.

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