Article

Loss of Atrx Affects Trophoblast Development and the Pattern of X-Inactivation in Extraembryonic Tissues

MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
PLoS Genetics (Impact Factor: 7.53). 05/2006; 2(4):e58. DOI: 10.1371/journal.pgen.0020058
Source: PubMed

ABSTRACT

Synopsis
ATRX belongs to a class of proteins that may modify how DNA is packaged into chromatin, altering the accessibility of other proteins in the nucleus to DNA. In this way, ATRX is thought to influence gene expression. Mutations in the ATRX gene, which is located on the female sex chromosome (X), provided the first example of a human disease (ATR-X syndrome) associated with defects in such proteins. Affected males (XMUTY) have multiple developmental abnormalities in a wide variety of systems. Currently, it is not understood how proteins like ATRX influence cell biology. To address this question, the authors deleted the version of the gene in mice, Atrx. Although affected male mice (XMUTY) started to develop normally, they died early in development because they failed to form a normal placenta. In the placenta, female mice normally inactivate the X chromosome that they inherit from their fathers (Xp), so if females inherit from their mother an X chromosome (Xm) that bears the abnormal copy of Atrx (XmMUTXp), one would predict that, like affected males, they would fail to form a normal placenta. The authors unexpectedly found this not to be so. They showed, instead, that in such females the normal, paternally derived Atrx gene is active. This study has therefore demonstrated an important facet of X-chromosome imprinting.

Download full-text

Full-text

Available from: Lorraine Rose, Mar 20, 2014
  • Source
    • "DAXX can also act as a chaperon for the chromatin deposition of histone H3 variant H3.3 (Wong et al., 2010; Xue et al., 2003). Knocking out either Daxx or Atrx in mice was embryonic lethal (Garrick et al., 2006; Michaelson et al., 1999). Previous work has indicated that both DAXX and ATRX can localize to pericentric heterochromatin and telomeres in somatic cells and ESCs (Baumann et al., 2008; Emelyanov et al., 2010; Wong et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In mammals, DNA methylation is essential for protecting repetitive sequences from aberrant transcription and recombination. In some developmental contexts (e.g., preimplantation embryos) DNA is hypomethylated but repetitive elements are not dysregulated, suggesting that alternative protection mechanisms exist. Here we explore the processes involved by investigating the role of the chromatin factors Daxx and Atrx. Using genome-wide binding and transcriptome analysis, we found that Daxx and Atrx have distinct chromatin-binding profiles and are co-enriched at tandem repetitive elements in wild-type mouse ESCs. Global DNA hypomethylation further promoted recruitment of the Daxx/Atrx complex to tandem repeat sequences, including retrotransposons and telomeres. Knockdown of Daxx/Atrx in cells with hypomethylated genomes exacerbated aberrant transcriptional de-repression of repeat elements and telomere dysfunction. Mechanistically, Daxx/Atrx-mediated repression seems to involve Suv39h recruitment and H3K9 trimethylation. Our data therefore suggest that Daxx and Atrx safeguard the genome by silencing repetitive elements when DNA methylation levels are low. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Sep 2015 · Cell stem cell
  • Source
    • "To assess this, female SV129 mice carrying a floxed allele of the X chromosome-linked ATRX gene (Garrick et al., 2006) were crossed with castaneus males to generate a male (SV129 3 Cast) F1 ESC line, which would allow allelic discrimination . The SV129 3 Cast ATRX Flox ESCs were transduced with an adenoviral Cre-GFP cassette (AdCre) to generate ATRX KO cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Histone H3.3 is a replication-independent histone variant, which replaces histones that are turned over throughout the entire cell cycle. H3.3 deposition at euchromatin is dependent on HIRA, whereas ATRX/Daxx deposits H3.3 at pericentric heterochromatin and telomeres. The role of H3.3 at heterochromatic regions is unknown, but mutations in the ATRX/Daxx/H3.3 pathway are linked to aberrant telomere lengthening in certain cancers. In this study, we show that ATRX-dependent deposition of H3.3 is not limited to pericentric heterochromatin and telomeres but also occurs at heterochromatic sites throughout the genome. Notably, ATRX/H3.3 specifically localizes to silenced imprinted alleles in mouse ESCs. ATRX KO cells failed to deposit H3.3 at these sites, leading to loss of the H3K9me3 heterochromatin modification, loss of repression, and aberrant allelic expression. We propose a model whereby ATRX-dependent deposition of H3.3 into heterochromatin is normally required to maintain the memory of silencing at imprinted loci. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Apr 2015 · Cell Reports
  • Source
    • "The affected males exhibit severe intellectual disability, and multiple congenital abnormalities involving genital and skeletal development, as well as a characteristic facial appearance and many have alpha thalassaemia an anaemia which, in these individuals, is due to reduced alpha globin gene expression. Extensive studies in mouse have shown that absence of full- length ATRX leads to defective development of the trophoblast [4], loss of neurons in the CNS [5], lack of proliferation of myoblasts [6] and Sertoli cells [7] as well as abnormal mitosis [8] and meiosis [9]. It is unclear however how all these diverse effects result from ATRX dysfunction. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The chromatin remodeling protein ATRX, which targets tandem repetitive DNA, has been shown to be required for expression of the alpha globin genes, for proliferation of a variety of cellular progenitors, for chromosome congression and for the maintenance of telomeres. Mutations in ATRX have recently been identified in tumours which maintain their telomeres by a telomerase independent pathway involving homologous recombination thought to be triggered by DNA damage. It is as yet unknown whether there is a central underlying mechanism associated with ATRX dysfunction which can explain the numerous cellular phenomena observed. There is, however, growing evidence for its role in the replication of various repetitive DNA templates which are thought to have a propensity to form secondary structures. Using a mouse knockout model we demonstrate that ATRX plays a direct role in facilitating DNA replication. Ablation of ATRX alone, although leading to a DNA damage response at telomeres, is not sufficient to trigger the alternative lengthening of telomere pathway in mouse embryonic stem cells.
    Full-text · Article · Mar 2014 · PLoS ONE
Show more