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

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          Abstract

          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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          Most cited references25

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          A map of the cis-regulatory sequences in the mouse genome.

          The laboratory mouse is the most widely used mammalian model organism in biomedical research. The 2.6 × 10(9) bases of the mouse genome possess a high degree of conservation with the human genome, so a thorough annotation of the mouse genome will be of significant value to understanding the function of the human genome. So far, most of the functional sequences in the mouse genome have yet to be found, and the cis-regulatory sequences in particular are still poorly annotated. Comparative genomics has been a powerful tool for the discovery of these sequences, but on its own it cannot resolve their temporal and spatial functions. Recently, ChIP-Seq has been developed to identify cis-regulatory elements in the genomes of several organisms including humans, Drosophila melanogaster and Caenorhabditis elegans. Here we apply the same experimental approach to a diverse set of 19 tissues and cell types in the mouse to produce a map of nearly 300,000 murine cis-regulatory sequences. The annotated sequences add up to 11% of the mouse genome, and include more than 70% of conserved non-coding sequences. We define tissue-specific enhancers and identify potential transcription factors regulating gene expression in each tissue or cell type. Finally, we show that much of the mouse genome is organized into domains of coordinately regulated enhancers and promoters. Our results provide a resource for the annotation of functional elements in the mammalian genome and for the study of mechanisms regulating tissue-specific gene expression.
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            ChIP-seq accurately predicts tissue-specific activity of enhancers.

            A major yet unresolved quest in decoding the human genome is the identification of the regulatory sequences that control the spatial and temporal expression of genes. Distant-acting transcriptional enhancers are particularly challenging to uncover because they are scattered among the vast non-coding portion of the genome. Evolutionary sequence constraint can facilitate the discovery of enhancers, but fails to predict when and where they are active in vivo. Here we present the results of chromatin immunoprecipitation with the enhancer-associated protein p300 followed by massively parallel sequencing, and map several thousand in vivo binding sites of p300 in mouse embryonic forebrain, midbrain and limb tissue. We tested 86 of these sequences in a transgenic mouse assay, which in nearly all cases demonstrated reproducible enhancer activity in the tissues that were predicted by p300 binding. Our results indicate that in vivo mapping of p300 binding is a highly accurate means for identifying enhancers and their associated activities, and suggest that such data sets will be useful to study the role of tissue-specific enhancers in human biology and disease on a genome-wide scale.
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              DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA.

              Mammals use DNA methylation for the heritable silencing of retrotransposons and imprinted genes and for the inactivation of the X chromosome in females. The establishment of patterns of DNA methylation during gametogenesis depends in part on DNMT3L, an enzymatically inactive regulatory factor that is related in sequence to the DNA methyltransferases DNMT3A and DNMT3B. The main proteins that interact in vivo with the product of an epitope-tagged allele of the endogenous Dnmt3L gene were identified by mass spectrometry as DNMT3A2, DNMT3B and the four core histones. Peptide interaction assays showed that DNMT3L specifically interacts with the extreme amino terminus of histone H3; this interaction was strongly inhibited by methylation at lysine 4 of histone H3 but was insensitive to modifications at other positions. Crystallographic studies of human DNMT3L showed that the protein has a carboxy-terminal methyltransferase-like domain and an N-terminal cysteine-rich domain. Cocrystallization of DNMT3L with the tail of histone H3 revealed that the tail bound to the cysteine-rich domain of DNMT3L, and substitution of key residues in the binding site eliminated the H3 tail-DNMT3L interaction. These data indicate that DNMT3L recognizes histone H3 tails that are unmethylated at lysine 4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2.
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                Author and article information

                Journal
                Nature
                Nature
                1476-4687
                0028-0836
                Sep 14 2016
                : 537
                : 7621
                Affiliations
                [1 ] Department of Microbiology, Oslo University Hospital, Rikshospitalet, NO-0027 Oslo, Norway.
                [2 ] Ludwig Institute for Cancer Research, La Jolla, California 92093, USA.
                [3 ] Department of Gynecology, Section for Reproductive Medicine, Oslo University Hospital, Rikshospitalet, NO-0027, Oslo, Norway.
                [4 ] The Biotech Research and Innovation Centre and Centre for Epigenetics, University of Copenhagen, DK-2200 Copenhagen, Denmark.
                [5 ] Norwegian Transgenic Centre, Institute of Basic Medical Sciences, University of Oslo, NO-0317 Oslo, Norway.
                [6 ] Department of Tumor Biology and Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, NO-0424 Oslo, Norway.
                [7 ] Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway.
                [8 ] Department of Nutrition, Faculty of Medicine, Institute of Basic Medical Sciences, University of Oslo, NO-0027 Oslo, Norway.
                [9 ] Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, California 92093, USA.
                [10 ] UCSD Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
                [11 ] Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, NO-0317 Oslo, Norway.
                Article
                nature19360
                10.1038/nature19360
                27626377
                98793278-58f3-4312-9ae1-ae4bd4d5fbdd
                History

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