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

Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
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.
    Full-text · Article · Nov 2013 · Epigenetics & Chromatin
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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.
    Full-text · Article · Jul 2013 · Nucleic Acids Research
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    • "In turn, H3K9me3 is known to recruit HP1. Thus, both DNA methylation and histone methylation can immediately be reinstated after replication (for review, seeWallace and Orr-Weaver 2005;Groth et al. 2007). "
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    ABSTRACT: The progression of pluripotent stem cells to differentiated cell lineages requires major shifts in cell differentiation programs. In both mammals and higher plants, this process appears to be controlled by a dedicated set of transcription factors, many of which are kingdom specific. These divergent transcription factors appear to operate, however, together with a shared suite of factors that affect the chromatin state. It is of major importance to investigate whether such shared global control mechanisms indicate a common mechanistic basis for preservation of the stem cell state, initiation of differentiation programs, and coordination of cell state transitions.
    Preview · Article · Feb 2009 · Cold Spring Harbor Symposia on Quantitative Biology
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