CpG Methylation Modifies the Genetic Stability of Cloned Repeat Sequences

Nichol, K.; Pearson, Christopher E.

doi:10.1101/gr.74502

Cited by 54 publications

(44 citation statements)

References 63 publications

(108 reference statements)

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“…In bacterial and SV40 cell systems, the SCA1 and FRAXA clones containing interrupted repeat tracts are more stable than clones containing pure repeats of similar length (29). 3 Our data show the ability of interruptions to amend the nucleosome assembly of both repeats from opposite strengths to a level closer to that of non-repetitive genetically stable sequences, suggest-3 K. N. Edamura and C. E. Pearson, unpublished data.…”

Section: Discussionmentioning

confidence: 71%

“…In the absence of aberrant CpG methylation, CGG deletions can occur in the male germ line during development of a FRAXA fetus (26), whereas the expanded and methylated repeats are postnatally stable. Similarly, the absence of CpG methylation may enhance CGG deletions in the somatic tissues of high functioning FRAXA males that inherited an expanded CGG tract that had experienced only partial aberrant CpG methylation (27,28) There is some suggestion that the effects of CpG methylation on instability are mediated through replication (29). 2 Modulation of CpG methylation and histone modifications can affect cytogenetic fragile site expression and transcriptional activity at the FRAXA locus.…”

mentioning

confidence: 99%

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Effect of CAT or AGG Interruptions and CpG Methylation on Nucleosome Assembly upon Trinucleotide Repeats on Spinocerebellar Ataxia, Type 1 and Fragile X Syndrome*

Mulvihill¹,

Edamura

Hagerman

et al. 2005

Journal of Biological Chemistry

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Nucleosome packaging regulates many aspects of DNA metabolism and is thought to mediate genetic instability and transcription of expanded trinucleotide repeats. Both instability and transcription are sensitive to repeat length, tract purity, and CpG methylation. CAT or AGG interruptions within the (CAG) n or (CGG) n tracts of spinocerebellar ataxia, type 1 or fragile X syndrome, respectively, confer increased genetic stability to the repeats. We report the formation of nucleosomes on sequences containing pure and interrupted (CAG) n and (CGG) n repeats having lengths above and below the genetic stability thresholds. Increased lengths of pure repeats led to increased and decreased propensities for nucleosome assembly on the (CAG) n and (CGG) n repeats, respectively. CpG methylation of the CGG repeat further reduced assembly. CAT interruptions in (CAG) n tracts decreased nucleosome assembly. In contrast, AGG interruptions in (CGG) n tracts did not affect assembly by hypoacetylated histones. The latter observation was unaltered by CpG methylation of the repeats. However, nucleosome assembly by hyperacetylated histones on interrupted CGG tracts was increased relative to pure tracts and this effect was abolished by CpG methylation. Thus, CAT or AGG interruptions can modulate the ability of (CAG) n and (CGG) n tracts to assemble into chromatin and the effect of the AGG interruptions is dependent upon both the methylation status of the DNA and the acetylation status of the histones. Compared with the genetically unstable pure repeats, both interruptions permit a propensity of nucleosome assembly closer to that of random (genetically stable) sequences, suggesting an association of nucleosome assembly of trinucleotide repeats and genetic instability.

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Section: Discussionmentioning

confidence: 71%

mentioning

confidence: 99%

Effect of CAT or AGG Interruptions and CpG Methylation on Nucleosome Assembly upon Trinucleotide Repeats on Spinocerebellar Ataxia, Type 1 and Fragile X Syndrome*

Mulvihill¹,

Edamura

Hagerman

et al. 2005

Journal of Biological Chemistry

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“…Evidence for participation of trans factors in repeat instability has been hard to come by. Among cis factors the location of the repeat region relative to origin of replication and methylation status of DNA have been determined to play a role in maintaining stability (17,19,35). How these processes may affect expansion is intriguing.…”

Section: Resultsmentioning

confidence: 99%

Analysis of DNA Replication Intermediates Suggests Mechanisms of Repeat Sequence Expansion

Veeraraghavan

Rossi

Bambara

2003

Journal of Biological Chemistry

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We previously developed a system to investigate the mechanism of repeat sequence expansion during eukaryotic Okazaki fragment processing. Upstream and downstream primers were annealed to a complementary template to overlap across a CAG repeat region. Annealing by the competing primers lead to structural intermediates that ligated to expand the repeat segment. When an equal number of repeats overlapped on the upstream and downstream primers, a 2-fold expansion was expected, but no expansion occurred. We show here that such substrates do not expand irrespective of their repeat length. To reveal mechanism, we tested different hairpin loop intermediates expected to form and facilitate ligation. Substrates configured to form large loops in either the upstream or downstream primer alone allowed expansion. Large or small fixed position single loops allowed expansion when located at least six nucleotides up-or downstream of the nick. Fixed loops in both primers, simulating a double loop intermediate, allowed expansion as long as each loop was nine nucleotides from the nick. Thus, neither the double loop configuration required to form with equal length overlaps nor the large single loop configuration are fundamental structural impediments to expansion. We propose a model for the expansion mechanism based on the relative stabilities of single loop, double loop, hairpin, and flap intermediates that is consistent with the observed expansion efficiency of equal and unequal overlap substrates. The model suggests that the equilibrium concentration of double loop intermediates is so vanishingly small that they are not likely contributors to sequence expansion.Repeat sequences are distributed widely in all organisms, forming the micro-and mini-satellite regions of their chromosomal DNAs (1). Triplet repeat sequences have attracted particular attention, because they are involved in pathogenesis of at least 14 neurological disorders (2). Of interest are the CAG, CGG, and GAA repeat tracts that are present in the normal population in lengths of 10 -25 triplets and show significant length polymorphisms. In a subset of the population repeat lengths reach the relatively stable pre-mutational length of 30 -50 repeats, which then undergo large intergenerational expansion by mechanisms that are poorly understood. Repeat sequences present in coding regions expand to a smaller extent than repeats that are located in 3Ј-untranslated region or regulatory regions that show expansion into thousands of repeats (2).Locus-specific expansion of CAG/CTG and CGG/CCG sequences suggests that the instability is an inherent property of repeat DNA (3). One characteristic of such DNA is the ability of repeat sequences to slip and mispair because of partial selfcomplementarity in the region. This gives rise to secondary structures in DNA (4, 5). Although slip mispairing can occur at all repeat sequences, only GAA, CGG, and CTG repeats exhibit expansion in vivo (6). These sequences have the additional quality that they can form secondary structures with hig...

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“…The effects of DNA methylation may be multifaceted and extend to regions beyond methylatable sites (Hodges-Garcia and Hagerman, 1992;Zacharias, 1993;Nichol and Pearson, 2002). Recently, our laboratory has examined the association of CpG methylation with the stability of various repetitive elements, including mono-, di-, tri-, penta-and minisatellite sequences .…”

Section: Cpg Methylationmentioning

confidence: 99%

The contribution of <i>cis</i>-elements to disease-associated repeat instability: clinical and experimental evidence

Cleary

Pearson²

2003

Cytogenet Genome Res

126

132

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Alterations in the length (instability) of gene-specific microsatellites and minisatellites are associated with at least 35 human diseases. This review will discuss the various cis-elements that contribute to repeat instability, primarily through examination of the most abundant disease-associated repetitive element, trinucleotide repeats. For the purpose of this review, we define cis-elements to include the sequence of the repeat units, the length and purity of the repeat tracts, the sequences flanking the repeat, as well as the surrounding epigenetic environment, including DNA methylation and chromatin structure. Gender-, tissue-, developmental- and locus-specific cis-elements in conjunction with trans-factors may facilitate instability through the processes of DNA replication, repair and/or recombination. Here we review the available human data that supports the involvement of cis-elements in repeat instability with limited reference to model systems. In diverse tissues at different developmental times and at specific loci, repetitive elements display variable levels of instability, suggesting vastly different mechanisms may be responsible for repeat instability amongst the disease loci and between various tissues.

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CpG Methylation Modifies the Genetic Stability of Cloned Repeat Sequences

Cited by 54 publications

References 63 publications

Effect of CAT or AGG Interruptions and CpG Methylation on Nucleosome Assembly upon Trinucleotide Repeats on Spinocerebellar Ataxia, Type 1 and Fragile X Syndrome*

Effect of CAT or AGG Interruptions and CpG Methylation on Nucleosome Assembly upon Trinucleotide Repeats on Spinocerebellar Ataxia, Type 1 and Fragile X Syndrome*

Analysis of DNA Replication Intermediates Suggests Mechanisms of Repeat Sequence Expansion

The contribution of <i>cis</i>-elements to disease-associated repeat instability: clinical and experimental evidence

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