Wallace, J. A. & Orr-Weaver, T. L. Replication of heterochromatin: insights into mechanisms of epigenetic inheritance. Chromosoma 114, 389-402

Whitehead Institute, Cambridge, MA, 02142, USA.
Chromosoma (Impact Factor: 4.6). 01/2006; 114(6):389-402. DOI: 10.1007/s00412-005-0024-6
Source: PubMed


Heterochromatin is composed of tightly condensed chromatin in which the histones are deacetylated and methylated, and specific nonhistone proteins are bound. Additionally, in vertebrates and plants, the DNA within heterochromatin is methylated. As the heterochromatic state is stably inherited, replication of heterochromatin requires not only duplication of the DNA but also a reinstallment of the appropriate protein and DNA modifications. Thus replication of heterochromatin provides a framework for understanding mechanisms of epigenetic inheritance. In recent studies, roles have been identified for replication factors in reinstating heterochromatin, particularly functions for origin recognition complex, proliferating cell nuclear antigen, and chromatin-assembly factor 1 in recruiting the heterochromatin binding protein HP1, a histone methyltransferase, a DNA methyltransferase, and a chromatin remodeling complex. Potential mechanistic links between these factors are discussed. In some cells, replication of the heterochromatin is blocked, and in Drosophila this inhibition is mediated by a chromatin binding protein SuUR.

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    • "Hence, they do not necessarily alter the frequency of switching. Mutations in other regulators produce higher levels of the expression of otherwise silenced reporters [89,90], but it is hard to tell if modest loss of repression or frequent epigenetic conversions have yielded these results. "
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    ABSTRACT: The remarkable ability of many parasites to evade host immunity is the key to their success and pervasiveness. The immune evasion is directly linked to the silencing of the members of extended families of genes that encode for major parasite antigens. At any time only one of these genes is active. Infrequent switches to other members of the gene family help the parasites elude the immune system and cause prolonged maladies. For most pathogens, the detailed mechanisms of gene silencing and switching are poorly understood. On the other hand, studies in the budding yeast Saccharomyces cerevisiae have revealed similar mechanisms of gene repression and switching and have provided significant insights into the molecular basis of these phenomena. This information is becoming increasingly relevant to the genetics of the parasites. Here we summarize recent advances in parasite epigenetics and emphasize the similarities between S. cerevisiae and pathogens such as Plasmodium, Trypanosoma, Candida, and Pneumocystis. We also outline current challenges in the control and the treatment of the diseases caused by these parasites and link them to epigenetics and the wealth of knowledge acquired from budding yeast.
    Epigenetics & Chromatin 11/2013; 6(1):40. DOI:10.1186/1756-8935-6-40 · 5.33 Impact Factor
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    • "Such phenomena should not be linked to the switching mechanism. On the other hand, many studies have shown increased levels of expression of otherwise silenced reporters [reviewed in (3,12)]. These observations have often been attributed to ‘poor maintenance’ of gene silencing, meaning an elevated rate of S→A switches, or to incomplete repression of the gene in the PEV locus. "
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    ABSTRACT: Position-effect variegation (PEV) phenotypes are characterized by the robust multigenerational repression of a gene located at a certain locus (often called gene silencing) and occasional conversions to fully active state. Consequently, the active state then persists with occasional conversions to the repressed state. These effects are mediated by the establishment and maintenance of heterochromatin or euchromatin structures, respectively. In this study, we have addressed an important but often neglected aspect of PEV: the frequency of conversions at such loci. We have developed a model and have projected various PEV scenarios based on various rates of conversions. We have also enhanced two existing assays for gene silencing in Saccharomyces cerevisiae to measure the rate of switches from repressed to active state and vice versa. We tested the validity of our methodology in Δsir1 cells and in several mutants with defects in gene silencing. The assays have revealed that the histone chaperone Chromatin Assembly Factor I is involved in the control of epigenetic conversions. Together, our model and assays provide a comprehensive methodology for further investigation of epigenetic stability and position effects.
    Nucleic Acids Research 07/2013; 41(18). DOI:10.1093/nar/gkt623 · 9.11 Impact Factor
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    • "Its occurance correlates with methylation of both DNA at CpG dinucleotides, and histones, particularly tri-methylation of histone H3 on lysine 9 and H4 on lysine 20. One effector of this code is the heterochromatin protein HP-1, which binds preferentially to histone H3 methylated on lysine 9 [1]. We suggest that formation of this condensed state involves the chromatin remodelling factor dATRX and that this protein may act as an effector of the epigenetic code at the pericentric heterochromatin. "
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    ABSTRACT: Despite extensive study of heterochromatin, relatively little is known about the mechanisms by which such a structure forms. We show that the Drosophila homologue of the human alpha-thalassemia and mental retardation X-linked protein (dATRX), is important in the formation or maintenance of heterochromatin through modification of position effect variegation. We further show that there are two isoforms of the dATRX protein, the longer of which interacts directly with heterochromatin protein 1 (dHP-1) through a CxVxL motif both in vitro and in vivo. These two proteins co-localise at heterochromatin in a manner dependent on this motif. Consistent with this observation, the long isoform of the dATRX protein localises primarily to the heterochromatin at the chromocentre on salivary gland polytene chromosomes, whereas the short isoform binds to many sites along the chromosome arms. We suggest that the establishment of a regular nucleosomal organisation may be common to heterochromatin and transcriptionally repressed chromatin in other locations, and may require the action of ATP dependent chromatin remodelling factors.
    PLoS ONE 02/2008; 3(5):e2099. DOI:10.1371/journal.pone.0002099 · 3.23 Impact Factor
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