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


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


Available from: Lorraine Rose, Mar 20, 2014
15 Reads
  • 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.
    Cell Reports 04/2015; 11(3). DOI:10.1016/j.celrep.2015.03.036 · 8.36 Impact Factor
  • 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.
    PLoS ONE 03/2014; 9(3):e92915. DOI:10.1371/journal.pone.0092915 · 3.23 Impact Factor
  • Source
    • "This single focus co-localises with DNA damage response factor 53BP1 at the nuclear lamina, and forelimbs lacking Atrx have higher incidence of TUNEL staining[27]. However, loss of Atrx in this model caused only a slight increase in apoptotic cells compared to other tissues such as brain, trophoblast, muscle and Sertoli cells[20,21,23,44]. Thus, our findings suggest that the protective effect of ATRX against DNA damage and replicative stress is tissue-specific, and that skeletal tissues are more resistant to the effects of Atrx loss. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The chromatin remodelling protein ATRX is associated with the rare genetic disorder ATR-X syndrome. This syndrome includes developmental delay, cognitive impairment, and a variety of skeletal deformities. ATRX plays a role in several basic chromatin-mediated cellular events including DNA replication, telomere stability, gene transcription, and chromosome congression and cohesion during cell division. We have used a loss-of-function approach to directly investigate the role of Atrx in the adult skeleton in three different models of selective Atrx loss. We specifically targeted deletion of Atrx to the forelimb mesenchyme, to cartilage and to bone-forming osteoblasts. We previously demonstrated that loss of ATRX in forelimb mesenchyme causes brachydactyly while deletion in chondrocytes had minimal effects during development. We now show that targeted deletion of Atrx in osteoblasts causes minor dwarfism but does not recapitulate most of the skeletal phenotypes seen in ATR-X syndrome patients. In adult mice from all three models, we find that joints lacking Atrx are not more susceptible to osteoarthritis, as determined by OARSI scoring and immunohistochemistry. These results indicate that while ATRX plays limited roles during early stages of skeletal development, deficiency of the protein in adult tissues does not confer susceptibility to osteoarthritis.
    PLoS ONE 12/2013; 8(12):e85526. DOI:10.1371/journal.pone.0085526 · 3.23 Impact Factor
Show more