Polycomb function during oogenesis is required for mouse embryonic development

Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland.
Genes & development (Impact Factor: 10.8). 04/2012; 26(9):920-32. DOI: 10.1101/gad.188094.112
Source: PubMed


In mammals, totipotent embryos are formed by fusion of highly differentiated gametes. Acquisition of totipotency concurs with chromatin remodeling of parental genomes, changes in the maternal transcriptome and proteome, and zygotic genome activation (ZGA). The inefficiency of reprogramming somatic nuclei in reproductive cloning suggests that intergenerational inheritance of germline chromatin contributes to developmental proficiency after natural conception. Here we show that Ring1 and Rnf2, components of Polycomb-repressive complex 1 (PRC1), serve redundant transcriptional functions during oogenesis that are essential for proper ZGA, replication and cell cycle progression in early embryos, and development beyond the two-cell stage. Exchange of chromosomes between control and Ring1/Rnf2-deficient metaphase II oocytes reveal cytoplasmic and chromosome-based contributions by PRC1 to embryonic development. Our results strongly support a model in which Polycomb acts in the female germline to establish developmental competence for the following generation by silencing differentiation-inducing genes and defining appropriate chromatin states.

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    • "Because PRC1 and PRC2 directly regulate the repression of a large set of common target genes, different models of functional dependency between these complexes have been proposed over the years (Gao et al., 2012; Scelfo et al., 2014) that suggest a dominant role for the PRC1 repressive activity (Blackledge et al., 2014; Cooper et al., 2014). Whereas Ring1a and Ring1b can be redundant during development (del Mar Lorente et al., 2000; Voncken et al., 2003), the Ring1a/b double KO embryos are impaired at the two-cell stage (Posfai et al., 2012), highlighting the requirement to inactivate both proteins to fully uncover PRC1 biological roles. Despite the extensive literature on the role of PRC1 in regulating gene transcription, embryonic stem cell (ESC) differentiation , and development, the role of PRC1 activity in adult stem cells is still largely unexplored. "
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    ABSTRACT: Polycomb repressive complexes (PRCs) are among the most important gatekeepers of establishing and maintaining cell identity in metazoans. PRC1, which plays a dominant role in this context, executes its functions via multiple subcomplexes, which all contribute to H2AK119 mono-ubiquitination (H2Aubq). Despite our comprehensive knowledge of PRC1-dependent H2Aubq in embryonic stem cells and during early development, its role in adult stem cells still remains poorly characterized. Here we show that PRC1 activity is required for the integrity of the intestinal epithelium, regulating stem cell self-renewal via a cell-autonomous mechanism that is independent from Cdkn2a expression. By dissecting the PRC1-dependent transcription program in intestinal stem cells, we demonstrate that PRC1 represses a large number of non-lineage-specific transcription factors that directly affect β-catenin/Tcf transcriptional activity. Our data reveal that PRC1 preserves Wnt/β-catenin activity in adult stem cells to maintain intestinal homeostasis and supports tumor formation induced by the constitutive activation of this pathway.
    Cell stem cell 11/2015; DOI:10.1016/j.stem.2015.09.019 · 22.27 Impact Factor
    • "In addition to DNA damage checkpoints, malfunction of zygotic genome activation (ZGA) also causes two-cell stage arrest (Bultman et al., 2006; Posfai et al., 2012; Wu et al., 2003). When the expression of ZGA genes (Zeng et al., 2004; Zeng and Schultz, 2005) was examined by quantitative RT-PCR, the mRNA levels of ZGA genes such as Tdpoz1, Tdpoz3, Tdpoz4 increased. "
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    ABSTRACT: Mammalian early embryos maintain accurate genome integrity for proper development within a programmed timeline despite constant assaults on their DNA by replication, DNA demethylation and genetic defects transmitted from germ cells. However, how genome integrity is safeguarded during mammalian early embryonic development remains unclear. BCAS2 (Breast Carcinoma Amplified Sequence 2), a core component of the PRP19 complex involved in pre-mRNA splicing, plays an important role in the DNA damage response through the RPA complex, a key regulator in the maintenance of genome integrity. Currently, the physiological role of BCAS2 in mammals is unknown. We now report that BCAS2 responds to endogenous and exogenous DNA damage in mouse zygotes. Maternal depletion of BCAS2 compromises the DNA damage response in early embryos, leading to developmental arrest at the two- to four-cell stage accompanied by the accumulation of damaged DNA and micronuclei. Furthermore, BCAS2 mutants that are unable to bind RPA1 fail in DNA repair during the zygotic stage. In addition, phosphorylated RPA2 cannot localize to the DNA damage sites in mouse zygotes with disrupted maternal BCAS2. These data suggest that BCAS2 may function through the RPA complex during DNA repair in zygotes. Altogether, our results reveal that maternal BCAS2 maintains the genome integrity of early embryos and is essential for female mouse fertility.
    Development 10/2015; 142(22). DOI:10.1242/dev.129841 · 6.46 Impact Factor
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    • "This phenotype might reflect a defect in cell cycle regulation and/or cytokinesis and thus might reflect a general role of E(z) that is conserved during metazoan evolution. This might be also consistent with recent studies conducted in mice, showing that PcG components play a role in DNA replication, cell cycle progression and embryonic development starting from the 2-cell stage (Posfai et al., 2012). The early 4-cell stage embryonic defect observed through Ci-E(z) invalidation is concomitant to early effects on gene expression. "
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    ABSTRACT: The paradigm of developmental regulation by Polycomb group (PcG) proteins posits that they maintain silencing outside the spatial expression domains of their target genes, particularly of Hox genes, starting from mid embryogenesis. The Enhancer of zeste [E(z)] PcG protein is the catalytic subunit of the PRC2 complex, which silences its targets via deposition of the H3K27me3 mark. Here, we studied the ascidian Ciona intestinalis counterpart of E(z). Ci-E(z) is detected by immunohistochemistry as soon as the 2- and 4-cell stages as a cytoplasmic form and becomes exclusively nuclear thereafter, whereas the H3K27me3 mark is detected starting from the gastrula stage and later. Morpholino invalidation of Ci-E(z) leads to the total disappearance of both Ci-E(z) protein and its H3K27me3 mark. Ci-E(z) morphants display a severe phenotype. Strikingly, the earliest defects occur at the 4-cell stage with the dysregulation of cell positioning and mitotic impairment. At later stages, Ci-E(z)-deficient embryos are affected by terminal differentiation defects of neural, epidermal and muscle tissues, by the failure to form a notochord and by the absence of caudal nerve. These major phenotypic defects are specifically rescued by injection of a morpholino-resistant Ci-E(z) mRNA, which restores expression of Ci-E(z) protein and re-deposition of the H3K27me3 mark. As observed by qPCR analyses, Ci-E(z) invalidation leads to the early derepression of tissue-specific developmental genes, whereas late-acting developmental genes are generally down-regulated. Altogether, our results suggest that Ci-E(z) plays a major role during embryonic development in Ciona intestinalis by silencing early-acting developmental genes in a Hox-independent manner.
    Biology Open 08/2015; DOI:10.1242/bio.010835 · 2.42 Impact Factor
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