Methylation mosaicism of 5'-(CGG)n-3' repeats in fragile X, premutation and normal individuals

Genc, B; Müller-Hartmann, Herbert; Zeschnigk, Michael; Deissler, Helmut; Schmitz, Birgit; Majewski, F.; Gontard, Alexander von; Doerfler, Walter

doi:10.1093/nar/28.10.2141

Cited by 53 publications

(32 citation statements)

References 40 publications

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“…When the repeat nears this threshold, heterochromatin forms and spreads in a manner reminiscent of position effect variegation, the stochastic spreading of heterochromatin to adjacent euchromatic regions 23 . For instance, some individuals carrying FRAXA premutation alleles (harboring ~60-200 CGG repeats) display mosaic patterns of DNA methylation in different tissues 24 , whereas the full expansion (>200 CGGs) is associated with complete FMR1 promoter methylation 25 . The idea that repeats can induce heterochromatin spreading was directly tested in mice 26 .…”

Section: The Chromatin Environment Of Expanded Triplet Repeatsmentioning

confidence: 99%

Instability and chromatin structure of expanded trinucleotide repeats

2009

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Trinucleotide repeat expansion underlies at least 17 neurologic diseases. In affected individuals, the expanded locus is characterized by dramatic changes in chromatin structure and in repeat tract length. Interestingly, recent studies show that several chromatin modifiers, including a histone acetyltransferase, a DNA methyltransferase, and the transcription factor CTCF can modulate repeat instability. Here, we propose that the unusual chromatin structure of expanded repeats directly impacts their instability. We discuss several potential models for how this might occur, including a role for DNA repair-dependent epigenetic reprogramming in increasing repeat instability, and the capacity of epigenetic marks to alter sense and antisense transcription, thereby affecting repeat instability.

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Section: The Chromatin Environment Of Expanded Triplet Repeatsmentioning

confidence: 99%

Instability and chromatin structure of expanded trinucleotide repeats

2009

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“…"Highfunctioning" FRAXA patients display high levels of CGG length heterogeneity, with alleles lacking aberrant CpG methylation frequently containing 130 to 300 repeats, whereas longer tracts within the same tissue were methylated (Wohrle et al 1998). Completely and partially methylated CGG tracts as short as 20 to 100 repeats have also been observed (Allingham-Hawkins et al 1996;Tassone et al 1999;Genc et al 2000). It has been suggested that for both germline and somatic tissues, the absence of CpG methylation may enhance the deletion of (CGG)n repeats (Burman et al 1999;Helderman-van den Enden et al 1999;Salat et al 2000;Wohrle et al 2001).…”

Section: Cpg Methylation Stabilizes (Cgg)nmentioning

confidence: 99%

CpG Methylation Modifies the Genetic Stability of Cloned Repeat Sequences

Nichol¹,

Pearson²

2002

Genome Res.

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The genetic stability of tandemly repeated DNAs is affected by repeat sequence, tract length, tract purity, and replication direction. Alterations in DNA methylation status are thought to influence many processes of mutagenesis. By use of bacterial and primate cell systems, we have determined the effect of CpG methylation on the genetic stability of cloned di-, tri-, penta-and minisatellite repeated DNA sequences. Depending on the repeat sequence, methylation can significantly enhance or reduce its genetic stability. This effect was evident when repeat tracts were replicated from either direction. Unexpectedly, methylation of adjacent sequences altered the stability of contiguous repeat sequences void of methylatable sites. Of the seven repeat sequences investigated, methylation stabilized five, destabilized one, and had no effect on another. Thus, although methylation generally stabilized repeat tracts, its influence depended on the sequence of the repeat. The current results lend support to the notion that the biological consequences of CpG methylation may be affected through local alterations of DNA structure as well as through direct protein-DNA interactions. In vivo CpG methylation in bacteria may have technical applications for the isolation and stable propagation of DNA sequences that have been recalcitrant to isolation and/or analyses because of their extreme instability.

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“…An exception occurs in some high-functioning fragile X patients who display mosaicism for repeat length and methylation (24,71). Hypermethylated fragile X cells display homogeneous and stable repeat lengths, but unmethylated repeats are heterogeneous for repeat length and stability (9,20,85,86). Since the position of the FMR1 origin favors contraction events, the hypomethylation and consequent instability of the expanded repeats in spermatocytes may provide a mechanism by which the repeats contract in these cells.…”

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confidence: 99%