Instability and chromatin structure of expanded trinucleotide repeats

Dion, Vincent; Wilson, John H.

doi:10.1016/j.tig.2009.04.007

Cited by 106 publications

(116 citation statements)

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“…For example, mutations that affect CTCF binding at the H19/Igf2 locus were shown to result in serious human syndromes (289)(290)(291). Improper CTCF binding has also been linked to other diseases, such as Huntington's disease, where mutations that destabilize CTCF binding sites appear to cause trinucleotide repeat expansion (292)(293)(294).…”

Section: Ctcf As a Master Genome Organizermentioning

confidence: 99%

An Overview of Genome Organization and How We Got There: from FISH to Hi-C

Fraser

Williamson

Bickmore

et al. 2015

Microbiol Mol Biol Rev

206

174

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SUMMARY In humans, nearly two meters of genomic material must be folded to fit inside each micrometer-scale cell nucleus while remaining accessible for gene transcription, DNA replication, and DNA repair. This fact highlights the need for mechanisms governing genome organization during any activity and to maintain the physical organization of chromosomes at all times. Insight into the functions and three-dimensional structures of genomes comes mostly from the application of visual techniques such as fluorescence in situ hybridization (FISH) and molecular approaches including chromosome conformation capture (3C) technologies. Recent developments in both types of approaches now offer the possibility of exploring the folded state of an entire genome and maybe even the identification of how complex molecular machines govern its shape. In this review, we present key methodologies used to study genome organization and discuss what they reveal about chromosome conformation as it relates to transcription regulation across genomic scales in mammals.

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Section: Ctcf As a Master Genome Organizermentioning

confidence: 99%

An Overview of Genome Organization and How We Got There: from FISH to Hi-C

Fraser

Williamson

Bickmore

et al. 2015

Microbiol Mol Biol Rev

206

174

View full text Add to dashboard Cite

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“…Although not tested, it is possible that interference with CTCF binding, either by mutation of its target site or mutations in an interacting partner, may contribute to trinucleotide repeat diseases (Libby et al 2008). Defects in CTCF, and other genome organizers, may also play a key role in destabilizing expanded microsatellite repeats in other trinucleotide repeat diseases (reviewed in Dion and Wilson 2009). …”

Section: Satb1mentioning

confidence: 99%

Higher-order Genome Organization in Human Disease

Misteli¹

2010

Cold Spring Harbor Perspectives in Biology

201

155

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Genomes are organized into complex higher-order structures by folding of the DNA into chromatin fibers, chromosome domains, and ultimately chromosomes. The higher-order organization of genomes is functionally important for gene regulation and control of gene expression programs. Defects in how chromatin is globally organized are relevant for physiological and pathological processes. Mutations and transcriptional misregulation of several global genome organizers are linked to human diseases and global alterations in chromatin structure are emerging as key players in maintenance of genome stability, aging, and the formation of cancer translocations.

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“…Each of these processes exposes single strands of repeats, which can form secondary structures such as hairpins and slipped-strand duplexes (10,41), which are thought to be the key intermediates that trigger repeat instability. As if that were not enough diversity, additional identified contributors to instability include epigenetic modifications, chromatin structure, and local sequence effects (4,7). Thus, the molecular details of repeat instability, especially the number of relevant pathways and the interconnections among them, are not yet clear.…”

mentioning

confidence: 99%

Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells

Hubert

Lin

Dion

et al. 2011

Molecular and Cellular Biology

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Expanded trinucleotide repeats are responsible for a number of neurodegenerative diseases, such as Huntington disease and myotonic dystrophy type 1. The mechanisms that underlie repeat instability in the germ line and in the somatic tissues of human patients are undefined. Using a selection assay based on contraction of CAG repeat tracts in human cells, we screened the Prestwick chemical library in a moderately highthroughput assay and identified 18 novel inducers of repeat contraction. A subset of these compounds targeted pathways involved in the management of DNA supercoiling associated with transcription. Further analyses using both small molecule inhibitors and small interfering RNA (siRNA)-mediated knockdowns demonstrated the involvement of topoisomerase 1 (TOP1), tyrosyl-DNA phosphodiesterase 1 (TDP1), and single-strand break repair (SSBR) in modulating transcription-dependent CAG repeat contractions. The TOP1-TDP1-SSBR pathway normally functions to suppress repeat instability, since interfering with it stimulated repeat contractions. We further showed that the increase in repeat contractions when the TOP1-TDP1-SSBR pathway is compromised arises via transcription-coupled nucleotide excision repair, a previously identified contributor to transcription-induced repeat instability. These studies broaden the scope of pathways involved in transcription-induced CAG repeat instability and begin to define their interrelationships.

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Instability and chromatin structure of expanded trinucleotide repeats

Cited by 106 publications

References 91 publications

An Overview of Genome Organization and How We Got There: from FISH to Hi-C

An Overview of Genome Organization and How We Got There: from FISH to Hi-C

Higher-order Genome Organization in Human Disease

Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells

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