Histone Variants in Metazoan Development

Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Developmental Cell (Impact Factor: 9.71). 11/2010; 19(5):662-74. DOI: 10.1016/j.devcel.2010.10.014
Source: PubMed


Embryonic development is regulated by both genetic and epigenetic mechanisms, with nearly all DNA-templated processes influenced by chromatin architecture. Sequence variations in histone proteins, core components of chromatin, provide a means to generate diversity in the chromatin structure, resulting in distinct and profound biological outcomes in the developing embryo. Emerging literature suggests that epigenetic contributions from histone variants play key roles in a number of developmental processes such as the initiation and maintenance of pericentric heterochromatin, X-inactivation, and germ cell differentiation. Here, we review the role of histone variants in the embryo with particular emphasis on early mammalian development.

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Available from: Peter W Lewis, Sep 14, 2014
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    • "3. Results and discussion 3.1. Nucleosome structures with mouse TH2a and TH2b variants The histone variants TH2a and TH2b are abundantly expressed during spermatogenesis [2] [3] "
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    ABSTRACT: Histone variants TH2a and TH2b are highly expressed in testes, oocytes and zygotes. Our recent analysis suggested that these histone variants enhance the induced generation of pluripotent stem cells (iPSCs) when co-expressed along with four transcription factors, Oct3/4, Sox2, Klf4 and c-Myc (OSKM), and are associated with an open chromatin structure [1]. In the present study, we report the crystal structures of nucleosomes (NCPs) with the mouse histone variants, TH2a and TH2b. The structures revealed two significant changes, as compared to the canonical counterparts: fewer histone-DNA contacts and changes in dimer-dimer interactions between TH2a-TH2a' (L1-loop). In vivo studies with domain swapping and point mutants of the variants revealed that the residues in the histone tails and the TH2a-L1 loop are important for reprogramming. Taken together, our work indicates that the NCP variants with structural modifications and flexible tails are most likely important for enhanced reprogramming of functions. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 07/2015; 464(3). DOI:10.1016/j.bbrc.2015.07.070 · 2.30 Impact Factor
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    • "The transition to the first mitosis at the onset of pre-implantation embryo development is a unique and highly dynamic process, taking place in the absence of major transcriptional activity. The extensive chromatin remodeling of paternal and maternal genomes in the one cell zygote is quickly followed by active global DNA de-methylation of the paternal genome and results in the establishment of epigenetic asymmetry in which paternal and maternal pronuclei acquire a unique epigenetic landscape characterized by distinct DNA and histone methylation marks, and histone variants (Mayer et al., 2000b; Oswald et al., 2000; Santos et al., 2005; Santenard and Torres-Padilla, 2009; Banaszynski et al., 2010; Kota and Feil, 2010). Remarkably, epigenetic asymmetry is maintained during interphase in the two-cell embryo where distinct chromatin marks reveal the polar distribution of paternal and maternal genomes (Mayer et al., 2000a; Hayashi- Takanaka et al., 2011). "
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    ABSTRACT: A striking proportion of human cleavage-stage embryos exhibit chromosome instability (CIN). Notably, until now, no experimental model has been described to determine the origin and mechanisms of complex chromosomal rearrangements. Here, we examined mouse embryos deficient for the chromatin remodeling protein ATRX to determine the cellular mechanisms activated in response to CIN. We demonstrate that ATRX is required for silencing of major satellite transcripts in the maternal genome, where it confers epigenetic asymmetry to pericentric heterochromatin during the transition to the first mitosis. This stage is also characterized by a striking kinetochore size asymmetry established by differences in CENP-C protein between the parental genomes. Loss of ATRX results in increased centromeric mitotic recombination, a high frequency of sister chromatid exchanges and double strand DNA breaks, indicating the formation of mitotic recombination break points. ATRX-deficient embryos exhibit a twofold increase in transcripts for aurora kinase B, the centromeric cohesin ESCO2, DNMT1, the ubiquitin-ligase (DZIP3) and the histone methyl transferase (EHMT1). Thus, loss of ATRX activates a pathway that integrates epigenetic modifications and DNA repair in response to chromosome breaks. These results reveal the cellular response of the cleavage-stage embryo to CIN and uncover a mechanism by which centromeric fission induces the formation of large-scale chromosomal rearrangements. Our results have important implications to determine the epigenetic origins of CIN that lead to congenital birth defects and early pregnancy loss, as well as the mechanisms involved in the oocyte to embryo transition.
    Development 05/2015; 142(10). DOI:10.1242/dev.118927 · 6.46 Impact Factor
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    • "The chromosomes separate with half being extruded into the first polar body and the egg arrests once again, at metaphase II, until fertilisation (Holt et al., 2013; Jones et al., 2013). Following this event, the second polar body is extruded and the male and female pronuclei fuse to generate a zygote (Banaszynski et al., 2010). "
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    ABSTRACT: A finite number of oocytes are established within the mammalian ovary prior to birth to form a precious ovarian reserve. Damage to this limited pool of gametes by environmental factors such as cigarette smoke and its constituents therefore represents a significant risk to a woman's reproductive capacity. Although evidence from human studies to date implicates a detrimental effect of cigarette smoking on female fertility, these retrospective studies are limited and present conflicting results. In an effort to more clearly understand the effect of cigarette smoke, and its chemical constituents, on female fertility, a variety of in vivo and in vitro animal models have been developed. This article represents a systematic review of the literature regarding four of experimental model types: 1) direct exposure of ovarian cells and follicles to smoking constituents’ in vitro, 2) direct exposure of whole ovarian tissue with smoking constituents in vitro, 3) whole body exposure of animals to smoking constituents and 4) whole body exposure of animals to cigarette smoke. We summarise key findings and highlight the strengths and weaknesses of each model system, and link these to the molecular mechanisms identified in smoke-induced fertility changes.
    Toxicology and Applied Pharmacology 12/2014; 281(3):266–275. DOI:10.1016/j.taap.2014.10.010 · 3.71 Impact Factor
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