Unravelling heterochromatin: competition between positive and negative factors regulates accessibility

Dillon, Niall; Festenstein, Richard

doi:10.1016/s0168-9525(02)02648-3

Cited by 234 publications

(152 citation statements)

References 59 publications

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“…The phenomenon of position effect variegation (PEV) first indicated the dynamic and stochastic properties of chromatin [7]. PEV was originally described in flies as a mottled red and white eye phenotype [8].…”

Section: The Dynamic and Stochastic Properties Of Chromatinmentioning

confidence: 99%

Aging by epigenetics—A consequence of chromatin damage?

Sedivy

Gowrishankar

Adams

2008

Experimental Cell Research

137

102

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Chromatin structure is not fixed. Instead, chromatin is dynamic and is subject to extensive developmental and age-associated remodeling. In some cases, this remodeling appears to counter the aging and age-associated diseases, such as cancer, and extend organismal lifespan. However, stochastic non-deterministic changes in chromatin structure might, over time, also contribute to the break down of nuclear, cell and tissue function, and consequently aging and age-associated diseases.

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Section: The Dynamic and Stochastic Properties Of Chromatinmentioning

confidence: 99%

Aging by epigenetics—A consequence of chromatin damage?

Sedivy

Gowrishankar

Adams

2008

Experimental Cell Research

137

102

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“…However, mechanistic aspects are beginning to emerge: silencing can result from the juxtaposition of genes to centromeres in cis, as a result of chromosomal translocations or of the centromeric integration of transgenes [29]. Similarly, the recruitment of chromatin domains to centromeric heterochromatin in trans imposes silencing in Drosophila melanogaster [30,31], and histone modifying enzymes and polycomb proteins contribute to centromere-imposed gene silencing in D. melanogaster and in mammalian cells [31,32].…”

Section: The Significance Of Locus Repositioning To Centromeric Hetermentioning

confidence: 99%

Nuclear repositioning marks the selective exclusion of lineage‐inappropriate transcription factor loci during T helper cell differentiation

et al. 2004

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To address how heritable patterns of gene expression are acquired during the differentiation of Th1 and Th2 cells, we analyzed the nuclear position of lineage-restricted cytokine genes and their upstream regulators by 3-dimensional fluorescence in situ hybridization. During Th1 differentiation, GATA-3 and c-maf loci, which encode upstream regulators of Th2 cytokines, were progressively repositioned to centromeric heterochromatin as defined by a c-satellite repeat probe and/or the nuclear periphery, compartments that have been associated with transcriptional repression. A third transcription factor locus, T-bet, which controls Th1-specific programs, was subject to de novo CpG methylation in a Th2 cell clone. In contrast, we did not find repositioning of the cytokine gene loci IL-2, IL-3, IL-4 or IFN-c during T helper cell differentiation. Instead, IFN-c was constitutively associated with the nuclear periphery, even when primed for expression in Th1 cells. Our results suggest that Th1/Th2 lineage commitment and differentiation involve repositioning of the regulators of cytokine expression, rather than the cytokine genes themselves.

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“…Ample amount of data from comparative genomic hybridization showed that whole-arm imbalances are common in tumors (Struski et al, 2002). Second, centromeric heterochromatin encompasses multiple forms of inactive chromatin structure that can lead to gene silencing, so that translocations at centromeric or pericentromeric regions may result in gene deregulation (Dillon and Festenstein, 2002;Perrod and Gasser, 2003). We thus propose that centromeric instability represents one of the basic forms of genomic instability and may play a functional role in cancer development.…”

Section: Discussionmentioning

confidence: 95%

Impact of G2 checkpoint defect on centromeric instability

et al. 2010

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Centromeric instability is characterized by dynamic formation of centromeric breaks, deletions, isochromosomes and translocations, which are commonly observed in cancer. So far, however, the mechanisms of centromeric instability in cancer cells are still poorly understood. In this study, we tested the hypothesis that G 2 checkpoint defect promotes centromeric instability. Our observations from multiple approaches consistently support this hypothesis. We found that overexpression of cyclin B1, one of the pivotal genes driving G 2 to M phase transition, impaired G 2 checkpoint and promoted the formation of centromeric aberrations in telomerase-immortalized cell lines. Conversely, centromeric instability in cancer cells was ameliorated through reinforcement of G 2 checkpoint by cyclin B1 knockdown. Remarkably, treatment with KU55933 for only 2.5 h, which abrogated G 2 checkpoint, was sufficient to produce centromeric aberrations. Moreover, centromeric aberrations constituted the major form of structural abnormalities in G 2 checkpoint-defective ataxia telangiectasia cells. Statistical analysis showed that the frequencies of centromeric aberrations in G 2 checkpoint-defective cells were always significantly overrepresented compared with random assumption. As there are multiple pathways leading to G 2 checkpoint defect, our finding offers a broad explanation for the common occurrence of centromeric aberrations in cancer cells.

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Unravelling heterochromatin: competition between positive and negative factors regulates accessibility

Cited by 234 publications

References 59 publications

Aging by epigenetics—A consequence of chromatin damage?

Aging by epigenetics—A consequence of chromatin damage?

Nuclear repositioning marks the selective exclusion of lineage‐inappropriate transcription factor loci during T helper cell differentiation

Impact of G2 checkpoint defect on centromeric instability

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